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Thalamus L-Sign: A Potential Biomarker of Neonatal Partial, Prolonged Hypoxic-Ischemic Brain Injury or Hypoglycemic Encephalopathy?

Thalamus L-Sign: A Potential Biomarker of Neonatal Partial, Prolonged Hypoxic-Ischemic Brain... ORIGINAL RESEARCH PEDIATRICS Thalamus L-Sign: A Potential Biomarker of Neonatal Partial, Prolonged Hypoxic-Ischemic Brain Injury or Hypoglycemic Encephalopathy? S.K. Misser, J.W. Lotz, R. van Toorn, N. Mchunu, M. Archary, and A.J. Barkovich ABSTRACT BACKGROUND AND PURPOSE: Considerable overlap exists in the MR imaging features of hypoglycemic injury and hypoxic-ische- mic brain injury, with similar predilections for the occipital and parietal lobes. In partial, prolonged hypoxia-ischemia, there is corti- cal destruction at the interarterial watershed zones, and in concomitant hypoglycemia and hypoxia-ischemia, an exaggerated final common pathway injury occurs. We interrogated secondary white matter tract–based thalamic injury as a tool to separate pure injuries in each group. MATERIALS AND METHODS: A retrospective observational study of the MRIs of 320 children with a history of hypoxia-ischemia and/or hypoglycemia was undertaken with 3 major subgroups: 1) watershed-type hypoxic-ischemic injury, 2) neonatal hypoglycemia, and 3) both perinatal hypoxia-ischemia and proved hypoglycemia. Cerebral and thalamic injuries were assessed, particularly hyperin- tensity of the posterolateral margin of the thalami. A modified Poisson regression model was used to assess factors associated with such thalamic injury. RESULTS: Parieto-occipital injuries occurred commonly in patients with hypoglycemia and/or hypoxia-ischemia. Eighty-five of 99 (86%) patients with partial, prolonged hypoxia-ischemia exhibited the thalamus L-sign. This sign was also observed in patients who had both hypoglycemia and hypoxia-ischemia, predominantly attributable to the latter. Notably, the risk of a thalamus L-sign injury was 2.79 times higher when both the parietal and occipital lobes were injured compared with when they were not involved (95% CI, 1.25–6.23; P ¼ .012). The thalamus L-sign was not depicted in patients with pure hypoglycemia. CONCLUSIONS: We propose the thalamus L-sign as a biomarker of partial, prolonged hypoxia-ischemia, which is exaggerated in com- bined hypoglycemic/hypoxic-ischemic injury. ABBREVIATIONS: HGI ¼ hypoglycemic injury; HIBI ¼ hypoxic-ischemic brain injury he MR imaging features of hypoglycemic injury (HGI) and In pure HGI, without HIBI, some authors have demonstrated a Thypoxic-ischemic brain injury (HIBI) are well-documented. posterior-predominant pattern of cerebral injury with a predilec- 1-4 tion for the occipital and parietal lobes. Other studies have Received December 24, 2021; accepted after revision March 21, 2022. noted that the pattern of HGI may be more widespread and not From the Departments of Radiology (S.K.M.) and Pediatrics (M.A.), Faculty of Health 5 always limited to the parieto-occipital areas. In the partial, pro- Sciences, University of KwaZulu-Natal, Nelson R Mandela School of Medicine, Durban, South Africa; Lake Smit and Partners Inc (S.K.M.), Durban, South Africa; longed type of HIBI, destruction of the cortex typically involves Departments of Radiodiagnosis (J.W.L.) and Paediatrics and Child Health (R.v.T.), the interarterial anterior, posterior, and peri-Sylvian watershed Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, 6-10 South Africa; Biostatistics Research Unit (N.M.), South African Medical Research zones and the contiguous white matter. HIBI-associated tha- Council, Durban, South Africa; School of Mathematics, Statistics and Computer lamic injury has been less frequently described, and in this study, Sciences, (N.M.), University of KwaZulu-Natal, Pietermaritzburg, South Africa; Centre for the AIDS Programme of Research in South Africa (N.M.), Urban, South we attempted to investigate thalamic involvement in children Africa; and School of Medicine (A.J.B.), University of California, San Francisco, San with documented partial, prolonged HIBI, neonatal hypoglyce- Francisco, California. mia, or combined hypoxic-ischemic and hypoglycemic injuries. Please address correspondence to Shalendra Kumar Misser, MD, Department of Radiology, University of KwaZulu-Natal, Faculty of Health Sciences, Nelson R Mandela School of Medicine, Durban, South Africa, Lake Smit and Partners Inc, Suite 301-327, The Atrium, Overport City, Durban, South Africa; e-mail: shalendra.misser@lakesmit.co.za MATERIALS AND METHODS Indicates open access to non-subscribers at www.ajnr.org MR imaging studies performed on 320 term neonates with sus- pected HIBI and/or HGI were analyzed for specific anatomic pat- Indicates article with online supplemental data. http://dx.doi.org/10.3174/ajnr.A7511 terns of injury. The retrospective, multicenter nature of the study AJNR Am J Neuroradiol 43:919–25 Jun 2022 www.ajnr.org 919 A separate cohort of 13 patients (uppermost in Fig 1) with documented neonatal hypoglycemia was evaluated for thalamic and cerebral injuries, to assess pulvinar and cortical, especially parieto- occipital, injury. Each of these 13 patients had a similar set of MR imaging sequen- ces (as above). These studies were inde- pendently reviewed by S.K.M. and J.L. Blood glucose levels were documented in all neonates who had symptomatic hypoglycemia. Neonatal hypoglycemia was defined by a recorded plasma glucose value of ,1.8 mmol/L during the first 2 hours of life or ,2.6 mmol/L thereafter. Hypoxic- ischemic encephalopathy was excluded on the basis of the absence of fetal distress, normal findings on blood gas analysis, reassuring Apgar scores at 1 and 5 minutes, and the absence of multiorgan hypoxia. The third group of 10 patients (lower- FIG 1. Derivation of the 3 major study groups, the subgroups of HIBI, and the subtypes of water- most in Fig 1) included those in whom shed patterns of injury in patients who had partial, prolonged HIBI. both perinatal hypoxic-ischemic ence- phalopathy and hypoglycemia were docu- mented. Particular attention was paid to identification of injury to the watershed and the various clinical setups did not allow time standardization of zones and pulvinar involvement in these patients. The Apgar imaging; all imaging occurred after the acute phase of injury. scores together with documented perinatal hypoxia-ischemia and Imaging studies were conducted on 1.5T MR imaging scanners blood gas analyses confirmed HIE, and there was also recorded (Siemens). The sequences performed in all patients included sagittal hypoglycemia in all these children, either after birth or in the first 2 T1-weighted volumetric: 1-mm-slice GE (TR/TE = 1900/2.95 ms), days of life as per the criteria outlined above. coronal volumetric inversion recovery: 1.1-mm-slice spin-echo (TR/ Statistical Analysis TE = 4000/363 ms), axial T2-weighted, axial FLAIR, axial diffusion- Categoric variables of the key features of each partial, prolonged weighted/ADC, coronal inversion recovery through the temporal HIBI subtype and thalamic injury location were expressed as fre- lobes, axial susceptibility-weighted and coronal T2-weighted sequen- quencies and percentages and compared using either the x test ces were obtained in all patients. Ethics approval was obtained from or the Fisher exact test if there were ,5 observations in any cell. University of KwaZulu-Natal (BREC00001036/2020). A modified Poisson regression model was used to assess factors After anonymization, images were reviewed by 2 radiologists associated with pulvinar thalamic injury versus nil and atypical (S.K.M. and J.W.L. with 15 and 30 years of experience in neurora- diology respectively), who were blinded to all patient data. Brain subtypes combined. A 2-tailed P, .05 indicated statistical signifi- MR imaging findings were divided by consensus into 3 major cance. All statistical analyses were conducted using SAS, Version study subgroups (Fig 1). The HIBI subgroup was categorized into 9.4 (SAS Institute). 4 patterns; additionally, the partial prolonged HIBI group was further subdivided into 7 (Fig 1) watershed injury pattern sub- RESULTS types. We noted 3 categories of thalamic involvement: posterolat- The group of 99 term neonates with HIBI demonstrating partial, eral/pulvinar, atypical, and no thalamic injury. In particular, the prolonged patterns of injury were imaged in the chronic phase of first category referred to those patients with an injured pulvinar injury, with the averageage at thetimeof imaging being 6years. and the lateral margin of the thalamus abutting the posterior This sample (n = 99) included 41 female patients and 58 male limb of the internal capsule. In patients with a documented cen- patients and were categorized into 7 subtypes, as shown in Fig 1. tral (basal ganglia–thalamus) pattern or mixed-type HIBI (with Table 1 highlights the prevalence, type, and severity of thalamic partial, prolonged, and central patterns), there is often ventral 6,9 injury in children with each subtype of partial, prolonged HIBI in thalamic injury, usually of the ventral posterior lateral nuclei. relation to the cortical injuries located in the frontal, parietal, occi- In addition, assessment of the posterolateral aspect of the thalami pital, peri-Sylvian, and hindbrain regions. There was a high degree is difficult in patients who have had multilobar cystic encephalo- of correlation of the MR imaging features between both readers malacia with severe or total brain injury. Patients with these 3 with no major discrepant findings. Lobar involvement was shown patterns (central, mixed, and cystic encephalomalacia) of HIBI to be high across all 4 cerebral lobes in descending order: occipital were excluded, as well as those with incomplete clinical informa- tion and poor-quality images. (91.9%), parietal (89.9%), frontal (88.9%), and temporal lobes 920 Misser Jun 2022 www.ajnr.org Table 1: Key features of the 7 subtypes of partial prolonged/watershed HIBI Subtype 1 Subtype 2 Subtype 3 Subtype 4 Subtype 5 Subtype 6 Subtype 7 Overall Anterior + Peri- Peri- Peri-Sylvian Anterior + All 3 Anterior Sylvian Posterior Sylvian + Posterior Posterior Zones Lobe/Structure Features (n = 10) (n =1) (n =1) (n =6) (n = 15) (n =7) (n = 59) (n = 99) Thalamic injury Nil 1 (16.7) 3 (30.0) 4 (4.0) location (No.) (%) Atypical 2 (33.3) 7 (70.0) 1 (14.3) 10 (10.1) Thalamus 1 (100.0) 1 (100.0) 3 (50.0) 15 (100.0) 6 (85.7) 59 (100.0) 85 (85.9) L-sign Thalamus score Not/less 1 (100.0) 1 (100.0) 6 (100.0) 14 (93.9) 10 (100.0) 6 (85.7) 53 (89.8) 91 (91.9) (No.) (%) involved Markedly 1 (6.7) 1 (14.3) 6 (10.2) 8 (8.1) destroyed Parietal (No.) (%) Not involved 3 (50.0) 6 (60.0) 1 (14.3) 10 (10.1) Involved 1 (100.0) 1 (100.0) 3 (50.0) 15 (100.0) 4 (40.0) 6 (85.7) 59 (100.0) 89 (89.9) Occipital (No.) (%) Not involved 1 (100.0) 7 (70.0) 8 (8.1) Involved 1 (100.0) 6 (100.0) 15 (100.0) 3 (30.0) 7 (100.0) 59 (100.0) 91 (91.9) Frontal (No.) (%) Not involved 1 (100.0) 8 (53.3) 1 (10.0) 1 (1.7) 11 (11.1) Involved 1 (100.0) 6 (100.0) 7 (46.7) 9 (90.0) 7 (100.0) 58 (98.3) 88 (88.9) Temporal (No.) (%) Not involved 3 (20.0) 6 (60.0) 3 (42.9) 3 (5.1) 15 (15.2) Involved 1 (100.0) 1 (100.0) 6 (100.0) 12 (80.0) 4 (40.0) 4 (57.1) 56 (94.9) 84 (84.8) Cerebellum (No.) Not involved 1 (100.0) 4 (66.7) 10 (66.7) 7 (70.0) 5 (71.4) 40 (67.8) 67 (67.7) (%) Involved 1 (100.0) 2 (33.3) 5 (33.3) 3 (30.0) 2 (28.6) 19 (32.2) 32 (32.3) Brainstem (No.) Not involved 1 (100.0) 1 (100.0) 6 (100.0) 14 (93.3) 10 (100.0) 7 (100.0) 49 (83.1) 88 (88.9) (%) Involved 1 (6.7) 10 (16.9) 11 (11.1) None of the patients (n = 10) with isolated anterior watershed injury had a thalamus L-sign. In some cases, signal abnormalities were evident in the anterior thalamus, usually medially and ven- trally, but these never included the ventral posterior lateral nu- cleus. All patients (61/99) in subtypes 2, 3, and 7 showed a bilateral thalamus L-sign. When the anterior and peri-Sylvian watershed zones were involved together (in subtype 4), we noted that half of those patients had a positive thalamus L-sign, but in each of these, the sign was identified unilaterally, only on the side where the peri-Sylvian cortex was destroyed. One patient in sub- type 5 had a feint unilateral posterior thalamic hyperintensity on the side where the watershed cortex destruction was more pro- nounced, but this was not categorized as a thalamus L-sign. The rest of the patients in subtype 5 all demonstrated a bilateral thala- mus L-sign. One patient of subtype 6 did not demonstrate the sign; however, the anterior watershed zone was severely FIG 2. Axial T2-weighted images in a child with partial, prolonged destroyed in this instance, with only minimal posterior watershed HIBI demonstrating interarterial injuries at the peri-Sylvian (dashed involvement. This patient’s pattern of injury simulates that of white arrow) and posterior parieto-occipital (solid white arrows) watershed regions. Note the thalamus L-sign (curved arrows in A and subtype 1. highlighted by the loupe in a second patient in B). A key correlation is the concomitant injury at the posterolateral thalamus and the lobes involved in the watershed zones of the cer- ebrum. Therewerestatistically significantdifferences between the (84.8%) (Table 1). In the subgroup of patients who demonstrated thalamus L-sign injury versus the other types of injuries combined; all 3 watershed zone injuries (9/99), we found injury to the pos- in particular, injuries involving the parietal, occipital, and temporal terolateral margin of the thalamus (adjacent to the posterior limb lobes were significantly more prevalent in the thalamus L-sign of internal capsule) and posterior thalamic (pulvinar and lateral ge- injury compared with other thalamic injuries (nil and atypical) niculate) nuclei on both sides, shown in Fig 2,which we term the (Table 2). Critically, the risk of experiencing a thalamus L-sign– “thalamus L-sign.” Overall, the thalamus L-sign was present in type injury was 7.38 times higher when an occipital lobe injury was 86% (85/99) of patients with prolonged, partial HIBI. identified compared with when it was not involved (95% CI, 1.18– Furthermore, subtype 7 with involvement of all 3 watershed zones 46.23), and this finding was statistically significant (P = .033). was the most prevalent HIBI subtype among the 85 (69.4%) Similarly, the risk of experiencing a thalamus L-sign injury was patients demonstrating the thalamus L-sign injury. 3.07 times higher when a parietal injury was present compared AJNR Am J Neuroradiol 43:919–25 Jun 2022 www.ajnr.org 921 Table 2: Key features involved in thalamus L-sign injury compared with other thalamic injuries (nil and atypical) Lobe/Structure Features Thalamus L-Sign (n = 85) Other (n = 14) Overall (n = 99) P Value Thalamus score (No.) (%) Not/less involved 77 (90.6) 14 (100.0) 91 (91.9) ,.001 Markedly destroyed 8 (9.4) Parietal (No.) (%) Not involved 3 (3.5) 7 (50.0) 10 (10.1) ,.001 Involved 82 (96.5) 7 (50.0) 89 (89.9) Occipital (No.) (%) Not involved 1 (1.2) 7 (50.0) 8 (8.1) ,.001 Involved 84 (98.8) 7 (50.0) 91 (91.9) Frontal (No.) (%) Not involved 10 (11.8) 1 (7.1) 11 (11.1) 1.000 Involved 75 (88.2) 13 (92.9) 88 (88.9) Temporal (No.) (%) Not involved 9 (10.6) 6 (42.9) 15 (15.2) .007 Involved 76 (89.4) 8 (57.1) 84 (84.8) Cerebellum (No.) (%) Not involved 57 (67.1) 10 (71.4) 67 (67.7) 1.000 Involved 28 (32.9) 4 (28.6) 32 (32.3) Brainstem (No.) (%) Not involved 74 (87.1) 14 (100.0) 88 (88.9) .355 Involved 11 (12.9) 11 (11.1) watershed HIBI, in whom we consistently identified the thalamus Table 3: Factors associated with the thalamic L-sign injury L-sign. Lobe/Structure RR 95% CI P Value In the third group of 10 patients who sustained both HGI and Parietal 3.07 1.197.93 .020 HIBI, the thalamus L-sign was also observed in all patients on Occipital 7.38 1.1846.23 .033 MR imaging studies acquired at the average age of 5 years. The Frontal 0.94 0.761.15 .539 Temporal 1.51 0.992.29 .055 axial T2-weighted images of these patients are compiled in the Cerebellum 1.03 0.871.21 .738 Online Supplemental Data. The blood glucose levels, Apgar Brainstem 1.19 1.091.30 ,.001 scores at 1 and 5minutes, aswell asother clinical parameters of Parietal 1 occipital 2.79 1.256.23 .012 hypoxic-ischemic encephalopathy were documented in each Note:—RR indicates relative risk. child. When concomitant injury was incurred, there was an exag- gerated final common pathway injury through the dorsal aspect with when it was not involved (95% CI, 1.197.93), and this find- of the thalami, which manifested as an L-shaped hyperintensity ing was statistically significant (P = .020). Notably, the risk of expe- involving the pulvinar and lateral margin of the thalamus super- riencing a thalamus L-sign injury was 2.79 times higher when both imposed on features of watershed territory ischemic injury. This parietal and occipital injuries were involved compared with when pattern of injury (common to all patients in this subgroup) is they were not involved (95% CI, 1.256.23), and this finding was shown in 2 such examples in Fig 4. The degree of thalamic signal also statistically significant (P = .012) (Table 3). hyperintensity and volume loss was marked in all of these The risk of experiencing a thalamus L-sign injury was 1.19 patients. times higher when a brainstem injury was present compared with when it was not involved (95% CI, 1.09 1.30), and this finding was statistically significant (P, .001). The risk of experiencing a DISCUSSION 6,8-10 thalamus L-sign injury was also higher when the frontal lobe, tem- In partial, prolonged HIBI, especially affecting the posterior poral lobe, and cerebellar injuries were all present compared with and peri-Sylvian watershed zones, we have repeatedly shown when they were not involved; however, this finding was not statisti- involvement of the posterior and lateral aspects of the thalamus, cally significant at a 5% level of significance (Table 3). which we believe to be a highly sensitive biomarker. This thalamus The second major group of patients studied included those L-sign described here is consistently identified in children who with isolated hypoglycemic injury. This cohort comprised 13 have a perinatal, partial, prolonged pattern of HIBI. Additionally, term-gestation neonates with 9 males and 4 females. We noted we note that in our study, the thalamus L-sign was not observed in that in all of these patients with confirmed pure HGI (without patients who had isolated, pure HGI without HIBI. We, therefore, any documented hypoxic-ischemic injury), there was cerebral propose the thalamus L-sign as a possible biomarker for HIBI of injury identified with gray and white matter involvement (as the partial, prolonged subtype, particularly when the posterior shown in Fig 3 and the Online Supplemental Data), which watershed territories have been involved. Furthermore, in patients included collation of axial T2-weighted and FLAIR images (at the who have endured combined hypoglycemia and hypoxia-ischemia, level of the thalamus) for 10 selected patients in this subgroup. In the phenomenon is exaggerated, likely due to the compounded lack all these patients, we found cortical injuries, particularly involving of usable substrates for brain metabolism. the posterior watershed zones of the parietal and occipital lobes. The thalamus is a central hub serving to interconnect several The encephalomalacia seen in these brain areas on the chronic- brain structures to each other and to the cerebellum, spinal cord, phase imaging studies performed was largely indistinguishable 13 and peripheral nervous system. Injuries to the thalamus provide from that seen in children who had HIBI. We did not identify an- an indirect indication of tract-based injuries to other parts of the terior watershed cortical territory involvement in any of these 13 brain, and by analyzing the involved substrates, we can infer a patients. Of critical importance, the posterior thalami were never pattern of injury that can be assigned to a particular pathophysio- injured in any of these 13 children with HGI. This is a key distin- logic process. Thalamic involvement in the HIBI of the central 15,16 guishing feature from those children who had posterior subtype injury pattern is well-documented and typically 922 Misser Jun 2022 www.ajnr.org of the object through parietal lobe connections. The ventral stream pathway also begins with visual cortex input, which passes through the lateral geniculate nuclei (especially the parvocellular layer) and from there onward to the temporal lobe (for limbic and memory connections) or to the parietal lobe via the dorsal stream (for accu- rate object location and motion initiation). Jang et al performed a tract-based DTI analysis of the ascending reticular activating system in 14 children with HIBI. They demonstrated lower reticular activating system involvement in patients with impaired arousal. We believe that the posterolat- eral thalamic margin that we see in children with partial, pro- longed HIBI includes, in part, involvement of the thalamic extension of the reticular activating system, which is located in FIG 3. Axial T2-weighted images in 2 children with proved neonatal this portion of the thalamus. Some of the hyperintensity may well hypoglycemia. There is bilateral occipital lobe encephalomalacia (arrows) related to hypoglycemic brain injury. Note the absence of be due to Wallerian degeneration change adjacent to the poste- any thalamic injury. rior limb of internal capsule secondary to the white matter involvement in the parietal, occipital, and peri-Sylvian regions, which pass through these corticospinal long tracts. We have found that all those with HIBI who demonstrated posterior watershed involvement either on its own or with peri- Sylvian watershed zone involvement also had a high correlation with a positive thalamus L-sign. In fact, all 59 patients (100%) who had partial, prolonged HIBI, all with watershed zone involvement, showed the thalamus L-sign. In contrast, all those individuals with isolated anterior water- shed involvement did not demonstrate the thalamus L-sign. When the anterior watershed was associated with other water- shed territory involvement, we noted that the thalamus L-sign was often present, probably consequent to the more posterior cerebral injury. The posterior watershed territories supply axons that contribute to the projection fibers that traverse the centrum ovale, forceps major, and optic radiation. These white matter FIG 4. Combined hypoxic-ischemic and hypoglycemic brain injury in tracts and neural networks feed into the lateral geniculate nuclei 2 children with documented neonatal encephalopathy. Note the and the pulvinar of the thalami. We found the risk of experienc- exaggerated signal abnormality and thalamic volume loss (black ing a thalamus L-sign injury to be 2.79 times higher when the pa- arrows). There are multiple watershed areas (white arrows)demon- rietal and occipital injuries were involved compared with when strating encephalomalacia change. they were not involved (95% CI, 1.256.23), and this finding was statistically significant (P = .012) (Table 3). We speculate that the demonstrates sparing of the pulvinar and lateral margin of the involvement of these thalamic nuclei may well reflect Wallerian thalami. degeneration along these tracts. The pulvinar or hockey stick sign has been linked to other disor- The patterns of brain injury seen in partial, prolonged HIBI ders, including Fabry disease, avariant-type Creutzfeldt-Jakob have been found to be very similar to those of HGI, and there is 18 19 20 5,25 disease, status epilepticus, and Wernicke encephalopathy. In considerable overlap in the injuries in these 2 entities. Most contrast, in the cases described here, we found an inverted configu- studies involve heterogeneous groups of children with concomitant ration to the hockey stick, with a characteristically repeated L-shape or sequential hypoxic-ischemic and hypoglycemic brain injuries due to involvement of the posterior and lateral substrates of the having been sustained. Wong et al demonstrated that specific thalamus rather than the paramedian nuclei. The thalamic nuclei imaging findings could be identified for both hypoglycemia and involved, shown in Figs 2, 4, and 5, probably include the thalamic hypoxia-ischemia in term infants with neonatal encephalopathy. reticular nucleus (abutting the posterior limb of internal capsule), They showed an 82% positive predictive value for the radiologic di- the pulvinar nucleus, and the lateral geniculate nucleus. Typically, agnosis of hypoglycemic brain injury with selective posterior white these structures when contiguously involved lead to an L-shaped matter and pulvinar edema the most predictive of clinical hypogly- signal abnormality in the thalami. We postulated that these ana- cemia. In contrast, none of the patients with hypoglycemia in our tomic structures collaborate as a functional unit enabling the dorsal study demonstrated any signal abnormalities in the pulvinar or and ventral stream pathways that operate via multiple transthalamic posterolateral thalami. We suspect that the changes described by connections. The dorsal stream pathway is responsible for recog- Wong et al correspond to the third group in our study, in which a nition of objects in space and proposing or guiding subsequent final common pathway injury was found. This suggestion is based actions. This stream begins with the visual (occipital) cortex iden- on a listed limitation by the authors in that they were unable to tification of objects in the visual field, followed by spatial awareness separate HIBI from HGI in their cohort studied, and the described AJNR Am J Neuroradiol 43:919–25 Jun 2022 www.ajnr.org 923 FIG 5. The key thalamic nuclei identified as components of the thalamus L-sign (dotted line) include the pulvinar, the lateral geniculate nucleus, and the reticular formation nuclei. Illustration by Neil Northey. posterior thalamic injuries in that study were more likely represen- all patients. However, a strength noted in their study was the cor- tative of the mixed, final common pathway. relation between hypoglycemia and the predominant watershed Tam et al showed an increased risk of injury to the cortico- pattern of brain injury, resonating the findings of previous stud- spinal tracts in children who had perinatal hypoglycemia. Using ies. It has been shown that the combination of hypoglycemia multivariate logistic regression analysis to adjust for biomarkers andhypoxia-ischemia is associatedwithworse perinatal and 27,28 of HIBI, the authors described an association between corticospi- long-term outcomes, including mortality. The upshot of nal tract injury and neonatal hypoglycemia. These patients, how- anaerobic metabolism on a fetus that had hypoxia-ischemia is ever, were not children with isolated hypoglycemia; many inefficient energy production and the glucose that is available probably had HIBI, and the degree of corticospinal tract and is rapidly used, with attendant hypoglycemia and inadvertent other substrate injuries may largely be due to hypoxia-ischemia. lower energy output (1 glucose molecule yields 2 adenosine tri- An important conclusion raised by the same authors was the need phosphate molecules versus a 1:38 ratio in aerobic condi- for specific biomarkers to separate HIBI from HGI, something this tions). The difficulty has always been to separate the 2 study attempts to prove using the thalamus L-sign. Another limita- entities. We have shown that by using this thalamus-L sign tion of that study was the variability in the timing of blood glu- described here, we were able to possibly distinguish HIBI from cose measurement revealing hypoglycemia. This is a universal pure HGI. occurrence (which we also noted) with the timing of blood glu- A limitation of our study was the retrospective evaluation of cose monitoring and not a standardized practice. The variability patients who were born some years earlier, with a lack of standar- in neonatal glucose levels warrants investigation, with a view to dized recording of clinical information and timing of the MR imag- further establishing norms for the timing of the measurement ing studies. Lack of complete medical records and blood test results thereof. In our study, we were fortunate in that all the patients (blood gas and glucose levels) was an exclusion criterion. All that we identified with hypoglycemia had documented blood glu- patients included here had available medical records. The possibility cose levels either in the immediate neonatal period or in the first of having included other patients (if records were available) would days of life. have increased the subgroup numbers. It would possibly also This recommendation was echoed in the study by Basu et al, improve the validity of the study with larger groups, and such pro- in which patients were referred to a central hospital from outlying spective studies with timeous blood gas and glucose analyses would hospitals and early glycemic measurements were not obtained in be encouraged. 924 Misser Jun 2022 www.ajnr.org CONCLUSIONS 11. Narvey MR, Marks SD. The screening and management of newborns at risk for low blood glucose. 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Thalamus L-Sign: A Potential Biomarker of Neonatal Partial, Prolonged Hypoxic-Ischemic Brain Injury or Hypoglycemic Encephalopathy?

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American Journal of Neuroradiology
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© 2022 by American Journal of Neuroradiology. Indicates open access to non-subscribers at www.ajnr.org
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10.3174/ajnr.a7511
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Abstract

ORIGINAL RESEARCH PEDIATRICS Thalamus L-Sign: A Potential Biomarker of Neonatal Partial, Prolonged Hypoxic-Ischemic Brain Injury or Hypoglycemic Encephalopathy? S.K. Misser, J.W. Lotz, R. van Toorn, N. Mchunu, M. Archary, and A.J. Barkovich ABSTRACT BACKGROUND AND PURPOSE: Considerable overlap exists in the MR imaging features of hypoglycemic injury and hypoxic-ische- mic brain injury, with similar predilections for the occipital and parietal lobes. In partial, prolonged hypoxia-ischemia, there is corti- cal destruction at the interarterial watershed zones, and in concomitant hypoglycemia and hypoxia-ischemia, an exaggerated final common pathway injury occurs. We interrogated secondary white matter tract–based thalamic injury as a tool to separate pure injuries in each group. MATERIALS AND METHODS: A retrospective observational study of the MRIs of 320 children with a history of hypoxia-ischemia and/or hypoglycemia was undertaken with 3 major subgroups: 1) watershed-type hypoxic-ischemic injury, 2) neonatal hypoglycemia, and 3) both perinatal hypoxia-ischemia and proved hypoglycemia. Cerebral and thalamic injuries were assessed, particularly hyperin- tensity of the posterolateral margin of the thalami. A modified Poisson regression model was used to assess factors associated with such thalamic injury. RESULTS: Parieto-occipital injuries occurred commonly in patients with hypoglycemia and/or hypoxia-ischemia. Eighty-five of 99 (86%) patients with partial, prolonged hypoxia-ischemia exhibited the thalamus L-sign. This sign was also observed in patients who had both hypoglycemia and hypoxia-ischemia, predominantly attributable to the latter. Notably, the risk of a thalamus L-sign injury was 2.79 times higher when both the parietal and occipital lobes were injured compared with when they were not involved (95% CI, 1.25–6.23; P ¼ .012). The thalamus L-sign was not depicted in patients with pure hypoglycemia. CONCLUSIONS: We propose the thalamus L-sign as a biomarker of partial, prolonged hypoxia-ischemia, which is exaggerated in com- bined hypoglycemic/hypoxic-ischemic injury. ABBREVIATIONS: HGI ¼ hypoglycemic injury; HIBI ¼ hypoxic-ischemic brain injury he MR imaging features of hypoglycemic injury (HGI) and In pure HGI, without HIBI, some authors have demonstrated a Thypoxic-ischemic brain injury (HIBI) are well-documented. posterior-predominant pattern of cerebral injury with a predilec- 1-4 tion for the occipital and parietal lobes. Other studies have Received December 24, 2021; accepted after revision March 21, 2022. noted that the pattern of HGI may be more widespread and not From the Departments of Radiology (S.K.M.) and Pediatrics (M.A.), Faculty of Health 5 always limited to the parieto-occipital areas. In the partial, pro- Sciences, University of KwaZulu-Natal, Nelson R Mandela School of Medicine, Durban, South Africa; Lake Smit and Partners Inc (S.K.M.), Durban, South Africa; longed type of HIBI, destruction of the cortex typically involves Departments of Radiodiagnosis (J.W.L.) and Paediatrics and Child Health (R.v.T.), the interarterial anterior, posterior, and peri-Sylvian watershed Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, 6-10 South Africa; Biostatistics Research Unit (N.M.), South African Medical Research zones and the contiguous white matter. HIBI-associated tha- Council, Durban, South Africa; School of Mathematics, Statistics and Computer lamic injury has been less frequently described, and in this study, Sciences, (N.M.), University of KwaZulu-Natal, Pietermaritzburg, South Africa; Centre for the AIDS Programme of Research in South Africa (N.M.), Urban, South we attempted to investigate thalamic involvement in children Africa; and School of Medicine (A.J.B.), University of California, San Francisco, San with documented partial, prolonged HIBI, neonatal hypoglyce- Francisco, California. mia, or combined hypoxic-ischemic and hypoglycemic injuries. Please address correspondence to Shalendra Kumar Misser, MD, Department of Radiology, University of KwaZulu-Natal, Faculty of Health Sciences, Nelson R Mandela School of Medicine, Durban, South Africa, Lake Smit and Partners Inc, Suite 301-327, The Atrium, Overport City, Durban, South Africa; e-mail: shalendra.misser@lakesmit.co.za MATERIALS AND METHODS Indicates open access to non-subscribers at www.ajnr.org MR imaging studies performed on 320 term neonates with sus- pected HIBI and/or HGI were analyzed for specific anatomic pat- Indicates article with online supplemental data. http://dx.doi.org/10.3174/ajnr.A7511 terns of injury. The retrospective, multicenter nature of the study AJNR Am J Neuroradiol 43:919–25 Jun 2022 www.ajnr.org 919 A separate cohort of 13 patients (uppermost in Fig 1) with documented neonatal hypoglycemia was evaluated for thalamic and cerebral injuries, to assess pulvinar and cortical, especially parieto- occipital, injury. Each of these 13 patients had a similar set of MR imaging sequen- ces (as above). These studies were inde- pendently reviewed by S.K.M. and J.L. Blood glucose levels were documented in all neonates who had symptomatic hypoglycemia. Neonatal hypoglycemia was defined by a recorded plasma glucose value of ,1.8 mmol/L during the first 2 hours of life or ,2.6 mmol/L thereafter. Hypoxic- ischemic encephalopathy was excluded on the basis of the absence of fetal distress, normal findings on blood gas analysis, reassuring Apgar scores at 1 and 5 minutes, and the absence of multiorgan hypoxia. The third group of 10 patients (lower- FIG 1. Derivation of the 3 major study groups, the subgroups of HIBI, and the subtypes of water- most in Fig 1) included those in whom shed patterns of injury in patients who had partial, prolonged HIBI. both perinatal hypoxic-ischemic ence- phalopathy and hypoglycemia were docu- mented. Particular attention was paid to identification of injury to the watershed and the various clinical setups did not allow time standardization of zones and pulvinar involvement in these patients. The Apgar imaging; all imaging occurred after the acute phase of injury. scores together with documented perinatal hypoxia-ischemia and Imaging studies were conducted on 1.5T MR imaging scanners blood gas analyses confirmed HIE, and there was also recorded (Siemens). The sequences performed in all patients included sagittal hypoglycemia in all these children, either after birth or in the first 2 T1-weighted volumetric: 1-mm-slice GE (TR/TE = 1900/2.95 ms), days of life as per the criteria outlined above. coronal volumetric inversion recovery: 1.1-mm-slice spin-echo (TR/ Statistical Analysis TE = 4000/363 ms), axial T2-weighted, axial FLAIR, axial diffusion- Categoric variables of the key features of each partial, prolonged weighted/ADC, coronal inversion recovery through the temporal HIBI subtype and thalamic injury location were expressed as fre- lobes, axial susceptibility-weighted and coronal T2-weighted sequen- quencies and percentages and compared using either the x test ces were obtained in all patients. Ethics approval was obtained from or the Fisher exact test if there were ,5 observations in any cell. University of KwaZulu-Natal (BREC00001036/2020). A modified Poisson regression model was used to assess factors After anonymization, images were reviewed by 2 radiologists associated with pulvinar thalamic injury versus nil and atypical (S.K.M. and J.W.L. with 15 and 30 years of experience in neurora- diology respectively), who were blinded to all patient data. Brain subtypes combined. A 2-tailed P, .05 indicated statistical signifi- MR imaging findings were divided by consensus into 3 major cance. All statistical analyses were conducted using SAS, Version study subgroups (Fig 1). The HIBI subgroup was categorized into 9.4 (SAS Institute). 4 patterns; additionally, the partial prolonged HIBI group was further subdivided into 7 (Fig 1) watershed injury pattern sub- RESULTS types. We noted 3 categories of thalamic involvement: posterolat- The group of 99 term neonates with HIBI demonstrating partial, eral/pulvinar, atypical, and no thalamic injury. In particular, the prolonged patterns of injury were imaged in the chronic phase of first category referred to those patients with an injured pulvinar injury, with the averageage at thetimeof imaging being 6years. and the lateral margin of the thalamus abutting the posterior This sample (n = 99) included 41 female patients and 58 male limb of the internal capsule. In patients with a documented cen- patients and were categorized into 7 subtypes, as shown in Fig 1. tral (basal ganglia–thalamus) pattern or mixed-type HIBI (with Table 1 highlights the prevalence, type, and severity of thalamic partial, prolonged, and central patterns), there is often ventral 6,9 injury in children with each subtype of partial, prolonged HIBI in thalamic injury, usually of the ventral posterior lateral nuclei. relation to the cortical injuries located in the frontal, parietal, occi- In addition, assessment of the posterolateral aspect of the thalami pital, peri-Sylvian, and hindbrain regions. There was a high degree is difficult in patients who have had multilobar cystic encephalo- of correlation of the MR imaging features between both readers malacia with severe or total brain injury. Patients with these 3 with no major discrepant findings. Lobar involvement was shown patterns (central, mixed, and cystic encephalomalacia) of HIBI to be high across all 4 cerebral lobes in descending order: occipital were excluded, as well as those with incomplete clinical informa- tion and poor-quality images. (91.9%), parietal (89.9%), frontal (88.9%), and temporal lobes 920 Misser Jun 2022 www.ajnr.org Table 1: Key features of the 7 subtypes of partial prolonged/watershed HIBI Subtype 1 Subtype 2 Subtype 3 Subtype 4 Subtype 5 Subtype 6 Subtype 7 Overall Anterior + Peri- Peri- Peri-Sylvian Anterior + All 3 Anterior Sylvian Posterior Sylvian + Posterior Posterior Zones Lobe/Structure Features (n = 10) (n =1) (n =1) (n =6) (n = 15) (n =7) (n = 59) (n = 99) Thalamic injury Nil 1 (16.7) 3 (30.0) 4 (4.0) location (No.) (%) Atypical 2 (33.3) 7 (70.0) 1 (14.3) 10 (10.1) Thalamus 1 (100.0) 1 (100.0) 3 (50.0) 15 (100.0) 6 (85.7) 59 (100.0) 85 (85.9) L-sign Thalamus score Not/less 1 (100.0) 1 (100.0) 6 (100.0) 14 (93.9) 10 (100.0) 6 (85.7) 53 (89.8) 91 (91.9) (No.) (%) involved Markedly 1 (6.7) 1 (14.3) 6 (10.2) 8 (8.1) destroyed Parietal (No.) (%) Not involved 3 (50.0) 6 (60.0) 1 (14.3) 10 (10.1) Involved 1 (100.0) 1 (100.0) 3 (50.0) 15 (100.0) 4 (40.0) 6 (85.7) 59 (100.0) 89 (89.9) Occipital (No.) (%) Not involved 1 (100.0) 7 (70.0) 8 (8.1) Involved 1 (100.0) 6 (100.0) 15 (100.0) 3 (30.0) 7 (100.0) 59 (100.0) 91 (91.9) Frontal (No.) (%) Not involved 1 (100.0) 8 (53.3) 1 (10.0) 1 (1.7) 11 (11.1) Involved 1 (100.0) 6 (100.0) 7 (46.7) 9 (90.0) 7 (100.0) 58 (98.3) 88 (88.9) Temporal (No.) (%) Not involved 3 (20.0) 6 (60.0) 3 (42.9) 3 (5.1) 15 (15.2) Involved 1 (100.0) 1 (100.0) 6 (100.0) 12 (80.0) 4 (40.0) 4 (57.1) 56 (94.9) 84 (84.8) Cerebellum (No.) Not involved 1 (100.0) 4 (66.7) 10 (66.7) 7 (70.0) 5 (71.4) 40 (67.8) 67 (67.7) (%) Involved 1 (100.0) 2 (33.3) 5 (33.3) 3 (30.0) 2 (28.6) 19 (32.2) 32 (32.3) Brainstem (No.) Not involved 1 (100.0) 1 (100.0) 6 (100.0) 14 (93.3) 10 (100.0) 7 (100.0) 49 (83.1) 88 (88.9) (%) Involved 1 (6.7) 10 (16.9) 11 (11.1) None of the patients (n = 10) with isolated anterior watershed injury had a thalamus L-sign. In some cases, signal abnormalities were evident in the anterior thalamus, usually medially and ven- trally, but these never included the ventral posterior lateral nu- cleus. All patients (61/99) in subtypes 2, 3, and 7 showed a bilateral thalamus L-sign. When the anterior and peri-Sylvian watershed zones were involved together (in subtype 4), we noted that half of those patients had a positive thalamus L-sign, but in each of these, the sign was identified unilaterally, only on the side where the peri-Sylvian cortex was destroyed. One patient in sub- type 5 had a feint unilateral posterior thalamic hyperintensity on the side where the watershed cortex destruction was more pro- nounced, but this was not categorized as a thalamus L-sign. The rest of the patients in subtype 5 all demonstrated a bilateral thala- mus L-sign. One patient of subtype 6 did not demonstrate the sign; however, the anterior watershed zone was severely FIG 2. Axial T2-weighted images in a child with partial, prolonged destroyed in this instance, with only minimal posterior watershed HIBI demonstrating interarterial injuries at the peri-Sylvian (dashed involvement. This patient’s pattern of injury simulates that of white arrow) and posterior parieto-occipital (solid white arrows) watershed regions. Note the thalamus L-sign (curved arrows in A and subtype 1. highlighted by the loupe in a second patient in B). A key correlation is the concomitant injury at the posterolateral thalamus and the lobes involved in the watershed zones of the cer- ebrum. Therewerestatistically significantdifferences between the (84.8%) (Table 1). In the subgroup of patients who demonstrated thalamus L-sign injury versus the other types of injuries combined; all 3 watershed zone injuries (9/99), we found injury to the pos- in particular, injuries involving the parietal, occipital, and temporal terolateral margin of the thalamus (adjacent to the posterior limb lobes were significantly more prevalent in the thalamus L-sign of internal capsule) and posterior thalamic (pulvinar and lateral ge- injury compared with other thalamic injuries (nil and atypical) niculate) nuclei on both sides, shown in Fig 2,which we term the (Table 2). Critically, the risk of experiencing a thalamus L-sign– “thalamus L-sign.” Overall, the thalamus L-sign was present in type injury was 7.38 times higher when an occipital lobe injury was 86% (85/99) of patients with prolonged, partial HIBI. identified compared with when it was not involved (95% CI, 1.18– Furthermore, subtype 7 with involvement of all 3 watershed zones 46.23), and this finding was statistically significant (P = .033). was the most prevalent HIBI subtype among the 85 (69.4%) Similarly, the risk of experiencing a thalamus L-sign injury was patients demonstrating the thalamus L-sign injury. 3.07 times higher when a parietal injury was present compared AJNR Am J Neuroradiol 43:919–25 Jun 2022 www.ajnr.org 921 Table 2: Key features involved in thalamus L-sign injury compared with other thalamic injuries (nil and atypical) Lobe/Structure Features Thalamus L-Sign (n = 85) Other (n = 14) Overall (n = 99) P Value Thalamus score (No.) (%) Not/less involved 77 (90.6) 14 (100.0) 91 (91.9) ,.001 Markedly destroyed 8 (9.4) Parietal (No.) (%) Not involved 3 (3.5) 7 (50.0) 10 (10.1) ,.001 Involved 82 (96.5) 7 (50.0) 89 (89.9) Occipital (No.) (%) Not involved 1 (1.2) 7 (50.0) 8 (8.1) ,.001 Involved 84 (98.8) 7 (50.0) 91 (91.9) Frontal (No.) (%) Not involved 10 (11.8) 1 (7.1) 11 (11.1) 1.000 Involved 75 (88.2) 13 (92.9) 88 (88.9) Temporal (No.) (%) Not involved 9 (10.6) 6 (42.9) 15 (15.2) .007 Involved 76 (89.4) 8 (57.1) 84 (84.8) Cerebellum (No.) (%) Not involved 57 (67.1) 10 (71.4) 67 (67.7) 1.000 Involved 28 (32.9) 4 (28.6) 32 (32.3) Brainstem (No.) (%) Not involved 74 (87.1) 14 (100.0) 88 (88.9) .355 Involved 11 (12.9) 11 (11.1) watershed HIBI, in whom we consistently identified the thalamus Table 3: Factors associated with the thalamic L-sign injury L-sign. Lobe/Structure RR 95% CI P Value In the third group of 10 patients who sustained both HGI and Parietal 3.07 1.197.93 .020 HIBI, the thalamus L-sign was also observed in all patients on Occipital 7.38 1.1846.23 .033 MR imaging studies acquired at the average age of 5 years. The Frontal 0.94 0.761.15 .539 Temporal 1.51 0.992.29 .055 axial T2-weighted images of these patients are compiled in the Cerebellum 1.03 0.871.21 .738 Online Supplemental Data. The blood glucose levels, Apgar Brainstem 1.19 1.091.30 ,.001 scores at 1 and 5minutes, aswell asother clinical parameters of Parietal 1 occipital 2.79 1.256.23 .012 hypoxic-ischemic encephalopathy were documented in each Note:—RR indicates relative risk. child. When concomitant injury was incurred, there was an exag- gerated final common pathway injury through the dorsal aspect with when it was not involved (95% CI, 1.197.93), and this find- of the thalami, which manifested as an L-shaped hyperintensity ing was statistically significant (P = .020). Notably, the risk of expe- involving the pulvinar and lateral margin of the thalamus super- riencing a thalamus L-sign injury was 2.79 times higher when both imposed on features of watershed territory ischemic injury. This parietal and occipital injuries were involved compared with when pattern of injury (common to all patients in this subgroup) is they were not involved (95% CI, 1.256.23), and this finding was shown in 2 such examples in Fig 4. The degree of thalamic signal also statistically significant (P = .012) (Table 3). hyperintensity and volume loss was marked in all of these The risk of experiencing a thalamus L-sign injury was 1.19 patients. times higher when a brainstem injury was present compared with when it was not involved (95% CI, 1.09 1.30), and this finding was statistically significant (P, .001). The risk of experiencing a DISCUSSION 6,8-10 thalamus L-sign injury was also higher when the frontal lobe, tem- In partial, prolonged HIBI, especially affecting the posterior poral lobe, and cerebellar injuries were all present compared with and peri-Sylvian watershed zones, we have repeatedly shown when they were not involved; however, this finding was not statisti- involvement of the posterior and lateral aspects of the thalamus, cally significant at a 5% level of significance (Table 3). which we believe to be a highly sensitive biomarker. This thalamus The second major group of patients studied included those L-sign described here is consistently identified in children who with isolated hypoglycemic injury. This cohort comprised 13 have a perinatal, partial, prolonged pattern of HIBI. Additionally, term-gestation neonates with 9 males and 4 females. We noted we note that in our study, the thalamus L-sign was not observed in that in all of these patients with confirmed pure HGI (without patients who had isolated, pure HGI without HIBI. We, therefore, any documented hypoxic-ischemic injury), there was cerebral propose the thalamus L-sign as a possible biomarker for HIBI of injury identified with gray and white matter involvement (as the partial, prolonged subtype, particularly when the posterior shown in Fig 3 and the Online Supplemental Data), which watershed territories have been involved. Furthermore, in patients included collation of axial T2-weighted and FLAIR images (at the who have endured combined hypoglycemia and hypoxia-ischemia, level of the thalamus) for 10 selected patients in this subgroup. In the phenomenon is exaggerated, likely due to the compounded lack all these patients, we found cortical injuries, particularly involving of usable substrates for brain metabolism. the posterior watershed zones of the parietal and occipital lobes. The thalamus is a central hub serving to interconnect several The encephalomalacia seen in these brain areas on the chronic- brain structures to each other and to the cerebellum, spinal cord, phase imaging studies performed was largely indistinguishable 13 and peripheral nervous system. Injuries to the thalamus provide from that seen in children who had HIBI. We did not identify an- an indirect indication of tract-based injuries to other parts of the terior watershed cortical territory involvement in any of these 13 brain, and by analyzing the involved substrates, we can infer a patients. Of critical importance, the posterior thalami were never pattern of injury that can be assigned to a particular pathophysio- injured in any of these 13 children with HGI. This is a key distin- logic process. Thalamic involvement in the HIBI of the central 15,16 guishing feature from those children who had posterior subtype injury pattern is well-documented and typically 922 Misser Jun 2022 www.ajnr.org of the object through parietal lobe connections. The ventral stream pathway also begins with visual cortex input, which passes through the lateral geniculate nuclei (especially the parvocellular layer) and from there onward to the temporal lobe (for limbic and memory connections) or to the parietal lobe via the dorsal stream (for accu- rate object location and motion initiation). Jang et al performed a tract-based DTI analysis of the ascending reticular activating system in 14 children with HIBI. They demonstrated lower reticular activating system involvement in patients with impaired arousal. We believe that the posterolat- eral thalamic margin that we see in children with partial, pro- longed HIBI includes, in part, involvement of the thalamic extension of the reticular activating system, which is located in FIG 3. Axial T2-weighted images in 2 children with proved neonatal this portion of the thalamus. Some of the hyperintensity may well hypoglycemia. There is bilateral occipital lobe encephalomalacia (arrows) related to hypoglycemic brain injury. Note the absence of be due to Wallerian degeneration change adjacent to the poste- any thalamic injury. rior limb of internal capsule secondary to the white matter involvement in the parietal, occipital, and peri-Sylvian regions, which pass through these corticospinal long tracts. We have found that all those with HIBI who demonstrated posterior watershed involvement either on its own or with peri- Sylvian watershed zone involvement also had a high correlation with a positive thalamus L-sign. In fact, all 59 patients (100%) who had partial, prolonged HIBI, all with watershed zone involvement, showed the thalamus L-sign. In contrast, all those individuals with isolated anterior water- shed involvement did not demonstrate the thalamus L-sign. When the anterior watershed was associated with other water- shed territory involvement, we noted that the thalamus L-sign was often present, probably consequent to the more posterior cerebral injury. The posterior watershed territories supply axons that contribute to the projection fibers that traverse the centrum ovale, forceps major, and optic radiation. These white matter FIG 4. Combined hypoxic-ischemic and hypoglycemic brain injury in tracts and neural networks feed into the lateral geniculate nuclei 2 children with documented neonatal encephalopathy. Note the and the pulvinar of the thalami. We found the risk of experienc- exaggerated signal abnormality and thalamic volume loss (black ing a thalamus L-sign injury to be 2.79 times higher when the pa- arrows). There are multiple watershed areas (white arrows)demon- rietal and occipital injuries were involved compared with when strating encephalomalacia change. they were not involved (95% CI, 1.256.23), and this finding was statistically significant (P = .012) (Table 3). We speculate that the demonstrates sparing of the pulvinar and lateral margin of the involvement of these thalamic nuclei may well reflect Wallerian thalami. degeneration along these tracts. The pulvinar or hockey stick sign has been linked to other disor- The patterns of brain injury seen in partial, prolonged HIBI ders, including Fabry disease, avariant-type Creutzfeldt-Jakob have been found to be very similar to those of HGI, and there is 18 19 20 5,25 disease, status epilepticus, and Wernicke encephalopathy. In considerable overlap in the injuries in these 2 entities. Most contrast, in the cases described here, we found an inverted configu- studies involve heterogeneous groups of children with concomitant ration to the hockey stick, with a characteristically repeated L-shape or sequential hypoxic-ischemic and hypoglycemic brain injuries due to involvement of the posterior and lateral substrates of the having been sustained. Wong et al demonstrated that specific thalamus rather than the paramedian nuclei. The thalamic nuclei imaging findings could be identified for both hypoglycemia and involved, shown in Figs 2, 4, and 5, probably include the thalamic hypoxia-ischemia in term infants with neonatal encephalopathy. reticular nucleus (abutting the posterior limb of internal capsule), They showed an 82% positive predictive value for the radiologic di- the pulvinar nucleus, and the lateral geniculate nucleus. Typically, agnosis of hypoglycemic brain injury with selective posterior white these structures when contiguously involved lead to an L-shaped matter and pulvinar edema the most predictive of clinical hypogly- signal abnormality in the thalami. We postulated that these ana- cemia. In contrast, none of the patients with hypoglycemia in our tomic structures collaborate as a functional unit enabling the dorsal study demonstrated any signal abnormalities in the pulvinar or and ventral stream pathways that operate via multiple transthalamic posterolateral thalami. We suspect that the changes described by connections. The dorsal stream pathway is responsible for recog- Wong et al correspond to the third group in our study, in which a nition of objects in space and proposing or guiding subsequent final common pathway injury was found. This suggestion is based actions. This stream begins with the visual (occipital) cortex iden- on a listed limitation by the authors in that they were unable to tification of objects in the visual field, followed by spatial awareness separate HIBI from HGI in their cohort studied, and the described AJNR Am J Neuroradiol 43:919–25 Jun 2022 www.ajnr.org 923 FIG 5. The key thalamic nuclei identified as components of the thalamus L-sign (dotted line) include the pulvinar, the lateral geniculate nucleus, and the reticular formation nuclei. Illustration by Neil Northey. posterior thalamic injuries in that study were more likely represen- all patients. However, a strength noted in their study was the cor- tative of the mixed, final common pathway. relation between hypoglycemia and the predominant watershed Tam et al showed an increased risk of injury to the cortico- pattern of brain injury, resonating the findings of previous stud- spinal tracts in children who had perinatal hypoglycemia. Using ies. It has been shown that the combination of hypoglycemia multivariate logistic regression analysis to adjust for biomarkers andhypoxia-ischemia is associatedwithworse perinatal and 27,28 of HIBI, the authors described an association between corticospi- long-term outcomes, including mortality. The upshot of nal tract injury and neonatal hypoglycemia. These patients, how- anaerobic metabolism on a fetus that had hypoxia-ischemia is ever, were not children with isolated hypoglycemia; many inefficient energy production and the glucose that is available probably had HIBI, and the degree of corticospinal tract and is rapidly used, with attendant hypoglycemia and inadvertent other substrate injuries may largely be due to hypoxia-ischemia. lower energy output (1 glucose molecule yields 2 adenosine tri- An important conclusion raised by the same authors was the need phosphate molecules versus a 1:38 ratio in aerobic condi- for specific biomarkers to separate HIBI from HGI, something this tions). The difficulty has always been to separate the 2 study attempts to prove using the thalamus L-sign. Another limita- entities. We have shown that by using this thalamus-L sign tion of that study was the variability in the timing of blood glu- described here, we were able to possibly distinguish HIBI from cose measurement revealing hypoglycemia. This is a universal pure HGI. occurrence (which we also noted) with the timing of blood glu- A limitation of our study was the retrospective evaluation of cose monitoring and not a standardized practice. The variability patients who were born some years earlier, with a lack of standar- in neonatal glucose levels warrants investigation, with a view to dized recording of clinical information and timing of the MR imag- further establishing norms for the timing of the measurement ing studies. Lack of complete medical records and blood test results thereof. In our study, we were fortunate in that all the patients (blood gas and glucose levels) was an exclusion criterion. All that we identified with hypoglycemia had documented blood glu- patients included here had available medical records. The possibility cose levels either in the immediate neonatal period or in the first of having included other patients (if records were available) would days of life. have increased the subgroup numbers. It would possibly also This recommendation was echoed in the study by Basu et al, improve the validity of the study with larger groups, and such pro- in which patients were referred to a central hospital from outlying spective studies with timeous blood gas and glucose analyses would hospitals and early glycemic measurements were not obtained in be encouraged. 924 Misser Jun 2022 www.ajnr.org CONCLUSIONS 11. Narvey MR, Marks SD. The screening and management of newborns at risk for low blood glucose. Paediatr Child Health 2019;24:536–44 The vicious interplay between hypoxia and hypoglycemia and CrossRef Medline their attendant secondary inflammatory cascades leads to a com- 12. Basu P, Som S, Choudhuri N, et al. Contribution of the blood glu- bined final common pathway injury, especially in patients whose cose level in perinatal asphyxia. Eur J Pediatr 2009;168:833–38 mother had prolonged labor. The thalamus L-sign, we propose, is CrossRef Medline an indication of a partial, prolonged type of HIBI and occurs in 13. Hwang K, Bertolero MA, Liu WB, et al. The human thalamus is an integrative hub for functional brain networks. JNeurosci patients who have endured additional HGI. In the patients pre- 2017;37:5594–5607 CrossRef Medline sented here, who had documented, isolated, pure HGI without 14. Squarcina L, Bertoldo A, Ham TE, et al. A robust method for inves- HIBI, the thalamus L-sign was not observed. We, therefore, intro- tigating thalamic white matter tracts after traumatic brain injury. duce this sign as a possible biomarker for HIBI of the partial Neuroimage 2012;63:779–88 CrossRef Medline prolonged subtype, particularly when the posterior watershed ter- 15. Van Cauter S, Severino M, Ammendola R, et al. Bilateral lesions of the basal ganglia and thalami (central grey matter)-pictorial review. ritories have been involved. This phenomenon is exaggerated in Neuroradiology 2020;62:1565–605 CrossRef Medline patients with combined HGI and HIBI due to the compounded 16. Sie LT, van der Knaap MS, Oosting J, et al. MR patterns of hypoxic-is- lack of usable substrates for brain metabolism. Future prospec- chemic brain damage after prenatal, perinatal or postnatal asphyxia. tive studies, preferably with the MR imaging scans performed Neuropediatrics 2000;31:128–36 CrossRef Medline around the time of suspected perinatal injury, with clinical corre- 17. 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Journal

American Journal of Neuroradiology – American Journal of Neuroradiology

Published: Jun 1, 2022

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