Beneficial Effect of Pretreatment Hyperosmolality on Outcome in Severe Traumatic Brain Injury: Evidence from a South Korean Multicenter Registry and Propensity Score Matching Analysis.

BACKGROUND: Hyperosmolar therapy has long been a cornerstone in managing increased intracranial pressure and improving outcomes in severe traumatic brain injury (TBI). This therapy hinges on elevating serum osmolality, creating an osmotic gradient that draws excess water from the brain's cellular and interstitial compartments and effectively reducing cerebral edema. Given this information, we hypothesized that the serum hyperosmolality prior to any treatment could significantly impact the clinical outcomes of patients with severe TBI, potentially mitigating secondary cerebral edema after trauma. METHODS: Data were extracted from the Korean Multi-center Traumatic Brain Injury data bank, encompassing 4628 patients with TBI admitted between January 2016 and December 2018. Of these, 507 patients diagnosed with severe TBI (Glasgow Coma Scale score < 9) were selected for comprehensive analysis across four data domains: clinical, laboratory, initial computed tomography scan, and treatment. Serum osmolality was assessed prior to treatment, and the hyperosmolar group was defined by a pretreatment serum osmolality exceeding 320 mOsm/L, whereas favorable outcomes were characterized by a modified Rankin Scale score of ≤ 3 at 6 months after trauma. Multivariate regression with receiver operating characteristic curve analysis and propensity score matching were used to dissect the data set. RESULTS: Multivariate analysis showed serum osmolality is significantly associated with clinical outcome in patients with severe TBI (p < 0.001). The optimal cutoff value for predicting favorable outcome was 331 mOsm/L, with a sensitivity of 38.9% and a specificity of 87.7%. Notably, the propensity score matching analysis comparing patients with pretreatment serum hyperosmolality with those without indicated a markedly improved functional outcome in the former group (32.5% vs 18.8%, p = 0.025). CONCLUSIONS: The present study has uncovered a significant correlation between the pretreatment serum osmolality and the clinical outcomes of patients with severe TBI. These findings offer a novel perspective, indicating that a serum hyperosmolality prior to any treatment might potentially have a neuroprotective effect in patients with severe TBI.

The Implication of Elevated Serum Myoglobin Level in Acute Diabetic Complications of Ketoacidosis and Hyperglycemic Hyperosmolar State: A Real-World Study.

Objective: To investigate the implications of elevated myoglobin (MYO) in acute diabetic conditions of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). Materials and methods: This study integrates in-patient data from Shanghai Pudong Hospital from 2019 to 2023. Laboratory data were compared between stable T2D patients (without acute diabetic complications), DKA, and HHS patients. The multilinear regression explored variables relevant to the elevated MYO in DKA and HHS. The dynamics of MYO, the survival rate, and associated risk factors in HHS were determined. Results: Except for triglyceride, procalcitonin, low-density lipoprotein, islet cell autoimmune antibodies, N-terminal Pro-brain natriuretic peptide (NT-ProBNP), and brain natriuretic peptide (BNP), there were significant differences in age, gender distribution, duration of diabetes, type of diabetes, and other referred laboratory data (p<0.05). The age, gender, creatine kinase (CK), estimated glomerular filtration rate (eGFR), and free triiodothyronine (FT3) in DKA, whereas osmolar, uric acid (UA), and cardiac troponin I (cTNI) in the HHS, were significant determinants of elevated MYO, respectively (p<0.05). The dynamic of MYO in HHS was in line with the survival trend, where the percentage of death was 29.73%, and aging with higher procalcitonin levels was a key risk factor. Besides, the cumulative survival rates between patients with or without bone fracture or muscle injury were substantially different. Conclusion: This real-world study demonstrated DKA and HHS potentially have unique causes for increased MYO. By utilizing the appropriate regression parameters, we could forecast the progression of increased MYO in groups of DKA and HHS, while based on risk factors of aging, severity of infection, and different MYO sources, we could predict the prognosis of HHS.

Management of diabetes-related hyperglycaemic emergencies in advanced chronic kidney disease: Review of the literature and recommendations.

AIMS: Despite the substantial progress in the management of diabetes mellitus (DM), chronic kidney disease (CKD) remains one of the most common complications. Although uncommon, diabetic emergencies [diabetic ketoacidosis (DKA), hyperosmolar hyperglycaemic state (HHS)] can still occur in stage 4 and 5 CKD, at times with less typical clinical manifestations due to the altered pathophysiology, presence of chronic metabolic acidosis and effect of haemodialysis on glycaemic control and metabolic parameters. The purpose of this article is to review the current literature and provide recommendations for the diagnosis and treatment of DKA, euglycaemic DKA and HHS in people with advanced CKD. METHODS AND RESULTS: Guidance on the management of diabetes-related emergencies mainly focuses on individuals with preserved renal function or early-stage CKD. Existing literature is limited, and recommendations are based on expert opinions and case reports. Given the clinical need for amended guidelines for this population, we are proposing a management algorithm for DKA and HHS based on clinical and metabolic parameters. CONCLUSIONS: In this review article, we propose treatment algorithms for diabetes-related hyperglycaemic emergencies in people with advanced CKD. Further research is needed to validate our proposed algorithms.

Risk of chronic kidney disease in patients with a hyperglycemic crisis as the initial presentation of type 2 diabetes.

Limited data exist on long-term renal outcomes in patients with hyperglycemic crisis (HC) as initial type 2 diabetes presentation. We evaluated the risk of chronic kidney disease (CKD) development in those with concurrent HC at diagnosis. Utilizing Taiwan's insurance claims from adults newly diagnosed with type 2 diabetes during 2006-2015, we created HC and matched non-HC cohorts. We assessed incident CKD/diabetic kidney disease (DKD) by 2018's end, calculating the hazard ratio (HR) with the Cox model. Each cohort comprised 13,242 patients. The combined CKD and DKD incidence was two-fold higher in the HC cohort than in the non-HC cohort (56.47 versus 28.49 per 1000 person-years) with an adjusted HR (aHR) of 2.00 (95% confidence interval [CI] 1.91-2.10]). Risk increased from diabetic ketoacidosis (DKA) (aHR:1.69 [95% CI 1.59-1.79]) to hyperglycemic hyperosmolar state (HHS) (aHR:2.47 [95% CI 2.33-2.63]) and further to combined DKA-HHS (aHR:2.60 [95% CI 2.29-2.95]). Subgroup analysis in individuals aged ≥ 40 years revealed a similar trend with slightly reduced incidences and HRs. Patients with HC as their initial type 2 diabetes presentation face a higher CKD risk than do those without HC. Enhanced medical attention and customized interventions are crucial to reduce this risk.

Hyperosmolar Hyperglycemic State-Induced Hyperviscosity as a Catalyst for Multiple Embolic Strokes.

Hyperosmolar hyperglycemic state (HHS) is the most serious emergency in patients with uncontrolled diabetes mellitus. It has been associated with a prothrombotic state that increases the risk for ischemia in affected patients. Despite the literature on the risk of ischemic stroke in patients with chronic hyperglycemia being vast, there is not enough documentation on the risk of developing a stroke during a hyperglycemic crisis. We present a rare case of an 86-year-old male who was admitted with HHS whose hospital course was further complicated by multiple embolic strokes. Prompt recognition of cerebral infarction when it intertwines with HHS remains a challenging task. This case emphasizes the value of clinical vigilance in patients with this hyperglycemic crisis. Further research is needed to better understand what this prothrombotic state truly entails in these patients.

Diazoxide-related Hyperglycemic Hyperosmolar State in a Child With Kabuki Syndrome.

Diazoxide is a commonly used first-line medication for the treatment of hyperinsulinism. Hyperglycemia may occur with diazoxide use. However, hyperglycemic hyperosmolar state (HHS) secondary to diazoxide is an exceedingly rare but potentially life-threatening adverse effect. We present a case of a 2-year-old with Kabuki syndrome and hyperinsulinism on diazoxide. She presented with 4 days of fever, respiratory symptoms, and lethargy. She was influenza B positive. Initial workup indicated HHS, with an elevated serum glucose (47.1 mmol/L [847.8 mg/dL]; reference range 3.9-6.0 mmol/L; 70-108 mg/dL), serum osmolality (357 mmol/kg H2O; reference 282-300 mmol/kg H2O) but absent urine ketones and no metabolic acidosis (venous pH 7.34). Her course was complicated by an acute kidney injury. Management in the hospital included discontinuation of diazoxide and intravenous fluid resuscitation, following which hyperglycemia and hyperosmolarity resolved. No insulin therapy was required. She remained normoglycemic without diazoxide for 2 weeks but subsequently required restarting of diazoxide for hypoglycemia. This case highlights the need for early recognition and prompt management of diazoxide-related HHS to reduce negative outcomes. We present the first case report of a child with Kabuki syndrome and hyperinsulinism with diazoxide-induced HHS.

Risk factors for adverse outcomes in children with diabetic ketoacidosis.

OBJECTIVE: Develop a multivariable model to identify children with diabetic ketoacidosis (DKA) and/or hyperglycemic hyperosmolar state (HHS) at increased risk of adverse outcomes, and apply it to analyze adverse outcomes during and after the COVID-19 pandemic. DESIGN: Retrospective review of clinical data from 4565 admissions (4284 with DKA alone, 31 [0.7%] only HHS, 250 [5.4%] hyperosmolar DKA) to a large academic children's hospital from January 2010-June 2023. 2010-2019 data (N=3004) were used as a training dataset, and 2020-2021 (N=903) and 2022-2023 (N=658) data for validation. Death or intensive care unit stays >48 hours comprised a composite "Adverse Outcome" group. Risks for this composite outcome were assessed using generalized estimating equations. RESULTS: There were 47 admissions with Adverse Outcomes (1.5%) in 2010-2019, 46 (5.0%) in 2020-2021, and 16 (2.4%) in 2022-2023. Eight patients died (0.18%). Maximum serum glucose, initial pH and diagnosis of type 2 diabetes most strongly predicted Adverse Outcomes. The proportion of patients with type 2 diabetes was highest in 2020-2021. A multivariable model incorporating these factors had excellent discrimination (area under receiver operator characteristic curve [AUC] of 0.948) for the composite outcome in the training dataset, and similar predictive power (AUC 0.960 and 0.873) in the 2020-2021 and 2022-2023 validation datasets, respectively. In the full dataset, AUC for death was 0.984. CONCLUSIONS: Type 2 diabetes and severity of initial hyperglycemia and acidosis are independent risk factors for Adverse Outcomes, and explain the higher frequency of Adverse Outcomes during the COVID-19 pandemic. Risks decreased in January 2022-June 2023.

Recognizing Complications in Youth With Diabetes Admitted With Diabetic Ketoacidosis Versus Hyperglycemic Hyperosmolar State.

INTRODUCTION: We compare in-hospital complications in youth with isolated diabetic ketoacidosis (DKA) to youth with hyperosmolarity. METHOD: We reviewed medical records of youth (1-20 years) admitted over two years with DKA, hyperglycemic hyperosmolar state (HHS), and hyperosmolar DKA. We evaluated outcomes, including hospital length of stay, altered mental status (AMS), and acute kidney injury (AKI). RESULTS: Of 369 admissions, 334 had isolated DKA, 32 had hyperosmolar DKA, and three had isolated HHS. Hyperosmolar youth had longer length of stay, larger initial fluid boluses, more frequent pediatric intensive care unit admissions, and increased risk of AKI and AMS. The odds of AKI were positively associated with serum osmolality and negatively associated with new-onset diabetes mellitus (DM) compared with established DM. CONCLUSIONS: In youth with DM, hyperosmolarity increases acute complications compared with isolated DKA. Larger-scale studies are needed to identify ways to prevent acute complications in youth experiencing hyperglycemic emergencies.

Empagliflozin-Associated Pancreatitis in the Setting of Hyperglycemic Hyperosmolar Syndrome.

Acute pancreatitis is a prevalent gastrointestinal condition in the United States, with approximately 130,000 new cases annually, displaying a rising incidence. Severe cases, constituting 20% of instances, necessitate intensive care unit admission, associated with elevated mortality rates. While gallstones and chronic alcohol use are primary causes, certain medications, including ACE inhibitors, statins, hormone-replacement therapies, diuretics, hypoglycemic agents, and steroids, can induce pancreatitis. Notably, recent reports link empagliflozin, an SGLT-2 inhibitor used in managing type 2 diabetes, to pancreatitis, a rare complication in this drug class. This article details a case study of a 57-year-old African American man presenting with hyperglycemic hyperosmolar syndrome due to empagliflozin-induced pancreatitis, a novel sequela. The discussion underscores the role of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in diabetes management, emphasizing their advantages and associated complications. This report adds a unique dimension to the literature, emphasizing the importance of prompt identification and cessation of culpable agents to prevent adverse outcomes. This article aims to comprehensively address the prevalence and increasing incidence of acute pancreatitis in the United States. This report aims to assist healthcare professionals in recognizing and discontinuing causative agents, thereby providing valuable insights into the comprehension of drug-induced pancreatitis.

Understanding the Complexity of Hyperglycemic Emergencies: Exploring the Influence of the Type and Duration of Diabetes Mellitus and Its Impact on Mortality.

Background Diabetes mellitus remains a pressing global health issue, characterized by chronic metabolic dysfunction and the potential for life-threatening acute hyperglycemic emergencies. These emergencies, known as diabetic ketoacidosis and hyperosmolar hyperglycemic states, trigger a series of physiological disruptions. This article delves deeply into how the type and duration of diabetes mellitus affect the occurrence of hyperglycemic emergencies and mortality rates. Methods The study was conducted at the Institute of Internal Medicine, Rajiv Gandhi General Hospital, affiliated with Madras Medical College, spanning from July 2021 to December 2021. It encompassed both individuals newly diagnosed with diabetic ketoacidosis and patients already undergoing diabetic treatment who developed diabetic ketoacidosis and hyperosmolar hyperglycemic states. Results Within the study cohort of 110 patients, 37.27% were diagnosed with Type 1 diabetes mellitus, while 62.73% were classified as Type 2 diabetes mellitus patients. Among these individuals, 23.60% were newly diagnosed with diabetes, 22.70% had been diabetic for less than one year, 47.30% had a diabetic history of two to five years, and 6.40% had been diabetic for over six years. However, upon investigating the relationship between diabetes duration and mortality rate, no statistically significant findings were observed. Conclusion Hyperglycemic emergencies represent multifaceted clinical challenges influenced by the interplay of various factors, including the type and duration of the disease. By maintaining effective management of hyperglycemia from the outset and sustaining it throughout their lives, people with diabetes can improve their physical and mental health and reduce the likelihood of developing long-term complications that may negatively impact their overall well-being.

Cemiplimab-Induced Hyperosmolar Hyperglycemic State With Concurrent Diabetic Ketoacidosis in a Patient Receiving Treatment for Cutaneous Squamous Cell Carcinoma.

The immune checkpoint inhibitor (ICI) cemiplimab is a human monoclonal antibody used in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC) not amenable to surgery or radiation therapy. Although cemiplimab shows excellent efficacy with a good tolerability profile, it can cause side effects, including potentially life-threatening endocrinopathies. We discuss the case of a 77-year-old Caucasian female with CSCC treated with only three cycles of cemiplimab who presented with altered mental status and was found to have severe hyperglycemia, hyperosmolarity, ketonemia, glucosuria, and ketonuria concerning for hyperosmolar hyperglycemic syndrome (HHS) with concurrent diabetic ketoacidosis (DKA). The patient made a rapid recovery in the hospital while on standard therapies for HHS/DKA and cemiplimab was discontinued upon discharge. While there have been reports of cemiplimab-induced DKA, to our knowledge, this is the first reported case of cemiplimab-induced HHS-DKA. This report aims to shed light on cemiplimab-induced HHS-DKA and to underscore the need to elucidate the molecular mechanisms underlying ICI-induced diabetes mellitus (ICI-DM).

Fixed, Dilated, and Cannulated - Medical Management of Elevated Intracranial Pressures due to a Large Intracranial Hemorrhage in a Patient on Veno-Venous Extracorporeal Membrane Oxygenation: Case Report.

A 40-year-old woman presented with mediastinitis, necrotizing pancreatitis, and severe acute respiratory distress syndrome with refractory acidemia (pH 7.14) and hypercapnia (PaCO2 115 mmHg), requiring veno-venous extracorporeal membrane oxygenation (ECMO). Eight hours after cannulation, and rapid correction of PaCO2 to 44 mmHg, she was found to have bilaterally fixed and dilated pupils. Imaging showed a 60 mL left-sided temporoparietal intracranial hemorrhage with surrounding edema, 8 mm midline shift, intraventricular hemorrhage, and impending herniation. Decompressive hemicraniectomy was not offered due to concern for medical instability. After receiving a dose of mannitol, her pupillary and motor exam improved. An intracranial pressure (ICP) monitor was placed to guide hyperosmolar therapy administration, hemodynamic targets, and sweep gas titration. On hospital day (HD) 5, her ICP monitor was removed. Follow-up imaging revealed resolution of mass effect and no brainstem injury. She was subsequently extubated (HD 9) and discharged home (HD 40). One year after hospitalization, she is living at home with minimal residual deficits. This case highlights the utility of targeted, medical ICP management and importance of assessing response to conservative therapies when considering prognosis in patients on ECMO with severe acute brain injury.

Hypoglycemia during hyperosmolar hyperglycemic crises is associated with long-term mortality.

BACKGROUND: Previous research has indicated that hypoglycemia during hospitalization is a predictor of unfavorable outcomes in patients with diabetes. However, no studies have examined the long-term impact of hypoglycemia in adults admitted for hyperglycemic crises. The study was aimed to investigate the long-term implications of hypoglycemia during hyperosmolar hyperglycemic crises, particularly in terms of all-cause mortality. METHODS: This retrospective cohort study included 170 patients (82 men [48.2%], median age 72 years) admitted to a university hospital for hyperosmolar hyperglycemic crises, including pure hyperosmolar hyperglycemic states and hyperosmolar diabetic ketoacidoses. We separately investigated the prognostic significance of hypoglycemia on mortality during the initial intravenous insulin therapy phase and during the later subcutaneous insulin therapy phase, both during hospitalization and in the long term (median follow-up, 652 days; range 2-3460 days). RESULTS: Both hypoglycemia during the initial intravenous insulin therapy phase (observed in 26.5% of patients) and hypoglycemia during the later subcutaneous insulin therapy phase (observed in 52.7% of patients) were associated with long-term mortality. After adjusting for potential confounders, hypoglycemia during the initial intravenous insulin therapy phase remained associated with mortality (hazard ratio 2.10, 95% CI 1.27-3.46, p = 0.004). CONCLUSIONS: Hypoglycemia during hyperosmolar hyperglycemic crises is a marker of long-term mortality, especially when it occurs during the initial intravenous insulin therapy phase.

High versus low chloride load in adult hyperglycemic emergencies with acute kidney injury: a multicenter retrospective cohort study.

Hyperglycemic emergencies frequently lead to acute kidney injury (AKI) and require treatment with large amount of intravenous fluids. However, the effects of chloride loading on this population have not yet been investigated. We conducted a multicenter, retrospective, cohort study in 21 acute-care hospitals in Japan. The study included hospitalized adult patients with diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS) who had AKI upon arrival. The patients were classified into high and low chloride groups based on the amount of chloride administered within the first 48 h of their arrival. The primary outcome was recovery from AKI; secondary outcome was major adverse kidney events within 30 days (MAKE30), including mortality and prolonged renal failure. A total of 390 patients with AKI, including 268 (69%) with DKA and 122 (31%) with HHS, were included in the study. Using the criteria of Kidney Disease Improving Global Outcomes, the severity of AKI in the patients was Stage 1 (n = 159, 41%), Stage 2 (n = 121, 31%), and Stage 3 (n = 110, 28%). The analysis showed no significant difference between the two groups in recovery from AKI (adjusted hazard ratio, 0.96; 95% CI 0.72-1.28; P = 0.78) and in MAKE30 (adjusted odds ratio, 0.91; 95% CI 0.45-1.76; P = 0.80). Chloride loading with fluid administration had no significant impact on recovery from AKI in patients with hyperglycemic emergencies.Trial Registration This study was registered in the UMIN clinical trial registration system (UMIN000025393, registered December 23, 2016).

Hyperosmolar therapies for neurological deterioration in mild and moderate traumatic brain injury: towards new research.

The scoping review by Nicolò Marchesini and colleagues about the use of hyperosmolar therapies (HTs) in patients with traumatic brain injury (TBI) points out a significant gap in scientific literature regarding this topic. Although there are few high-quality recommendations, it is important to provide care under certain physiologic parameters. Through this letter we comment on the importance of guidelines to administer and monitor the use of HTs in the Neuro-ICU.

Inflammatory biomarkers predict higher risk of hyperglycemic crises but not outcomes in diabetic patients with COVID-19.

Background: Inflammation is a predictor of severe complications in patients with COVID-19 infection under a variety of clinical settings. A few studies suggested that COVID-19 infection was a trigger of hyperglycemic crises including diabetic ketoacidosis (DKA) and/or hyperglycemic hyperosmolar state (HHS). However, the association between inflammation and hyperglycemic crises in diabetic patients with COVID-19 infection is unclear. Methods: One hundred and twenty-four patients with type 2 diabetes mellitus (T2DM) and COVID-19 infection from January 2023 to March 2023 were retrospectively analyzed. Demographic, clinical, and laboratory data, especially inflammatory markers including white blood cell (WBC), neutrophils, neutrophil-to-lymphocyte ratio (NLR), c-reactive protein (CRP) and procalcitonin (PCT) were collected and compared between patients with or without DKA and/or HHS. Multivariable logistic regression analysis was conducted to explore the association between inflammatory biomarkers and the prevalence of hyperglycemic crises. Patients were followed up 6 months for outcomes. Results: Among 124 diabetic patients with COVID-19, 9 were diagnosed with DKA or HHS. Comparing COVID-19 without acute diabetic complications (ADC), patients with DKA or HHS showed elevated levels of c-reactive protein (CRP, P=0.0312) and procalcitonin (PCT, P=0.0270). The power of CRP and PCT to discriminate DKA or HHS with the area under the receiver operating characteristics curve (AUROC) were 0.723 and 0.794, respectively. Multivariate logistic regression indicated 1.95-fold and 1.97-fold increased risk of DKA or HHS with 1-unit increment of CRP and PCT, respectively. However, neither CRP nor PCT could predict poor outcomes in diabetic patients with COVID-19. Conclusion: In this small sample size study, we firstly found that elevated serum CRP and PCT levels increased the risk of hyperglycemic crises in T2DM patients with COVID-19 infection. More study is needed to confirm our findings.

Hypertonic Aerosols Hydrate Airways Longer and Reduce Acidification Risk with Nonpermeating Cation and Permeating Anion Salts.

Background: Hyperosmolar aerosols appear to promote or suppress upper airway dysfunction caused by dehydration in a composition-dependent manner. We sought to explore this composition dependence experimentally, in an interventional human clinical study, and theoretically, by numerical analysis of upper airway ion and water transport. Methods: In a double-blinded, placebo-controlled clinical study, phonation threshold pressure (PTP) was measured prenasal and postnasal inhalation of hypertonic aerosols of NaCl, KCl, CaCl2, and MgCl2 in seven human subjects. Numerical analysis of water and solute exchanges in the upper airways following deposition of these same aerosols was performed using a mathematical model previously described in the literature. Results: PTP decreased by 9%-22% relative to baseline (p < 0.05) for all salts within the first 30 minutes postadministration, indicating effective laryngeal hydration. Only MgCl2 reduced PTP beyond 90 minutes (21% below baseline at 2 hours postadministration). By numerical analysis, we determined that, while airway water volume up to 15 minutes postdeposition is dictated by osmolarity, after 30 minutes, divalent cation salts, such as MgCl2, better retain airway surface liquid (ASL) volume by slow paracellular clearance of the divalent cation. Fall of CFTR chloride flux with rise in ASL height, a promoter of airway acidification, appears to be a signature of permeating cation (NaCl) and nonpermeating anion (mannitol) aerosol deposition. For hypertonic aerosols that lack permeating cation and include permeating anion (CaCl2 and MgCl2), this acid-trigger signature does not exist. Conclusions: Nonpermeating cation and permeating anion hypertonic aerosols appear to hydrate upper airways longer and, rather than provoke, may reduce laryngeal dysfunction such as cough and bronchoconstriction.

The Dark side of the White Matter. Diffuse subcortical White Matter Hypointensity on T2/FLAIR: A systematic review of a frequently underrecognized sign.

BACKGROUND AND OBJECTIVES: Many reversible brain MRI abnormalities have been described, among these the most frequently reported are cortical hyperintensities on FLAIR/T2 occurring during seizures. Much less attention has been given to those situations where White Matter goes Dark: subcortical white matter hypointensity on T2/FLAIR. Our aim is to identify the medical condition "Dark White Matter" (DWM) is more frequently associated with. This is the first systematic review on DWM. METHODS: PubMed was searched in August 2023. Included studies were those reporting Diffuse Subcortical White Matter Hypointensity on T2/FLAIR. Mainly case reports were included. Individual patient-level data was included whenever available. Frequency measures of the different diseases were calculated. RESULTS: 56 studies were included, 228 patients were eligible for analysis. DWM happened in isolation, with no cortical abnormalities, in 71 cases and was associated with seizures in >61.4% of cases. The most frequently DWM-associated disease was Non-Ketotic Hyperglycaemic hyperosmolar state (NKH), followed by Encephalitis, Moyamoya disease, Genetic Causes, and Subdural Hematoma. Frequency of NKH was 32%. NKH was associated with seizures in 100% of cases and the most frequently involved lobe was the occipital one. When considering only the subgroup of patients with seizures, DWM was indicative of NKH in 51.4% of cases and Encephalitis in 26.4% of cases. Key limitations are heterogeneity and missing data. DISCUSSION: DWM is frequently underdiagnosed. This sign can exist alone and it is not merely a consequence of cortical involvement. Moreover, it has important implications, both diagnostic and therapeutic, as it is more frequently associated with NKH, especially in the context of seizures, where anti-seizure medication is not the first line of treatment. We also discuss the pathogenesis of DWM by finding a common link between the most frequently associated diseases.