Published online November 26, 2007
PEDIATRICS Vol. 120 No. 6 December 2007, pp. e1540-e1546 (doi:10.1542/peds.2007-0366)
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EXPERIENCE & REASON

Coma With Diffuse White Matter Hemorrhages in Juvenile Diabetic Ketoacidosis

Farid H. Mahmud, MDa, David A. Ramsay, MB, ChBb, Simon D. Levin, MDc, Ram N. Singh, MBBSd, Trevor Kotylak, MDe and Douglas D. Fraser, MD, PhDd

a Division of Pediatric Endocrinology
b Department of Pathology, Divisions of
c Pediatric Neurology
d Pediatric Critical Care Medicine
e Department of Radiology, Children's Hospital of Western Ontario, London, Ontario, Canada

ABSTRACT

Cerebral edema is the most common neurologic complication of diabetic ketoacidosis in children. A minority of young patients with intracerebral crises in diabetic ketoacidosis present with cerebrovascular accidents. We report 2 adolescent patients with diabetic ketoacidosis who presented with coma and diffuse white matter hemorrhages in the absence of either cerebral edema or cerebrovascular accidents. These 2 cases illustrate a novel clinical and neuropathologic description of diffuse white matter hemorrhages, possibly related to a cytotoxic process as the underlying mechanism. These case descriptions emphasize that pediatric patients with diabetic ketoacidosis and coma can present with pathology not related to either cerebral edema or cerebrovascular accidents.

Key Words: diabetes • DKA • hemorrhage • white matter changes

Abbreviations: CE, cerebral edema • DKA, diabetic ketoacidosis • SIR, systemic inflammatory response • GCS, Glasgow Coma Scale • CT, computed tomography; MRI, magnetic resonance imaging

Cerebral edema (CE) is a major complication associated with diabetic ketoacidosis (DKA) and occurs in 0.46% to 1.0% of episodes of DKA in children.1–3 Although rare, CE with DKA has a 21% to 24% mortality rate and a 10% to 26% rate of neurologic disability.1–3 Since the initial description that linked CE with DKA,4 numerous published reports (coupled with advances in neuroimaging) have refined our understanding that the neurologic complications of DKA should be described by using the broader term "intracerebral complications."5 Other intracerebral complications that occur with DKA include hemorrhage and arterial and venous thrombus formation, which have been estimated on the basis of clinical series as occurring in 10% of cases.5–14

Here we present 2 atypical cases of new-onset DKA with coma and diffuse white matter hemorrhages in the absence of radiologic or pathologic evidence of CE or cerebrovascular accidents. Both patients were profoundly acidotic and had greatly elevated serum ketone levels. One patient died, and a postmortem examination of the brain was performed; the other patient underwent a diagnostic brain biopsy and experienced a protracted recovery with lingering neuropsychological deficits. These cases demonstrate acute neurologic dysfunction with neuropathologic evidence of diffuse white matter injury, which we propose is secondary to cytotoxic factors related to metabolic abnormalities and the systemic inflammatory response (SIR).

CASE REPORTS

Patient1.
The patient was a previously healthy 11-year-old girl of aboriginal heritage who was living in a remote northern community. Her previous medical history was significant for obesity and normal test results of random fasting blood sugar and hemoglobin A1c performed 3 years earlier because of a strong family history of type 2 diabetes.

She presented to a nursing station in northern Ontario with labored, shallow breathing preceded by a 4-day history of emesis, lethargy, and influenza-like symptoms in the absence of fever. On initial examination, her weight was 102 kg, height was 172 cm, BMI was 34.5 kg/m2, respiratory rate was 22 breaths per minute, pulse was 128 per minute, blood pressure was 94/59 mmHg, temperature was 36.3°C, and Glasgow Coma Scale (GCS) score was 13. Her blood glucose level was 17 mmol/L (306 mg/dL), and results of a urine dipstick test were positive for ketones. A provisional diagnosis of DKA was made, and the patient was given 2 L of normal saline delivered intravenously over 2 hours and a single 10-U regular intravenous insulin push. Maintenance fluids (normal saline with 20 mEq/L KCl) were continued at 100 mL/hour. Because of the limited medical resources in her community, the patient was transferred to our tertiary care pediatric hospital by air ambulance. Approximately 9 hours after her initial presentation, while in flight, there was a rapid deterioration in her level of consciousness, and the plane was diverted to the nearest medical center. There she was intubated, ventilated, and given 100 g of intravenous mannitol followed by 500 mL of 3% saline, which resulted in 1000 mL of urine output but no improvement in her level of consciousness. In addition to intravenous saline boluses, dopamine was administered to treat her hypotension and poor perfusion.

On arrival at our hospital, the patient had a GCS score of 3 in the absence of sedation. She received fluid and further inotropic support to stabilize her blood pressure and perfusion (heart rate: 130 beats per minute; blood pressure: 80/30 mmHg). Her examination was negative for signs of trauma, her pupils were equal at 2 mm and reactive to light; results of fundoscopy were normal, and no abnormal brainstem signs were elicited. The remainder of her examination was normal except for a yellow vaginal discharge. She did not have acanthosis nigricans. Her laboratory data are summarized in Table 1.


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  		TABLE 1 Comparison of Clinical, Initial Laboratory, and Diagnostic Data

 
Broad-spectrum antibiotic and antifungal coverage was administered, and serum osmolality was corrected slowly over 36 hours. Computed tomography (CT) and MRI (Fig 1A and B) of the head were unremarkable. Serial electroencephalograms demonstrated a burst-suppression pattern consistent with profound encephalopathy. Imaging of the chest (radiography and CT) revealed interstitial pulmonary edema, and results of CT of her abdomen and pelvis were normal. There was no evidence for bacterial, fungal, or viral infection in cultures and polymerase chain reaction testing of her blood, urine, and cerebrospinal fluid (opening pressure: 25 mmH2O). Over the course of 3 days, the patient became euglycemic on insulin infusion but remained on inotropic support and was severely acidotic (pH < 7.1). Her condition rapidly progressed to acute renal failure. As dialysis was starting, a profound rise in her potassium level, despite concerted measures to treat hyperkalemia, resulted in ventricular tachycardia and asystole.


Figure 1
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  		FIGURE 1 Normal imaging and postmortem neuropathology findings (patient 1). A and B, Head MRI axial (fluid-attenuated inversion recovery) (A) and coronal view (T2) (B) images were normal. C–F, Gross neuropathology. Small white matter hemorrhages are indicated (arrows) in the anterior commissure (C), crura cerebri (D), a medullary pyramid (E), and the cervical spinal posterior column (F). G, Microscopic review of the central nervous system revealed numerous additional small microscopic vasculocentric lesions throughout the white matter (hematoxylin, eosin, and Luxol fast blue were used; 2 lesions are present and labeled 1 and 2). The gross and microscopic lesions had distinctive morphology. They were centered on small blood vessels (arrow), and there were markedly eosinophilic, sometimes asymmetric, inner rings formed by variable combinations of fibrin, necrotic tissue, neutrophils, macrophages, axonal debris, and red blood cells (arrowhead) and outer rings of pale white matter (asterisks) with scant inflammatory cells and no histological evidence of demyelination. H, Many of the neurones (white arrowheads indicate examples of neurones) were characterized by indistinct (or "muddy") cytoplasmic staining, vesicular ("watery") nuclear chromatin, and prominent perineuronal spaces (with homogeneous, faintly basophilic proteinaceous material, indicated by arrows). The perineuronal spaces probably represent swollen astrocytic processes. Although it is difficult to be sure of whether these changes were artifactual, they are otherwise nonspecific postmortem findings in the brains from cases of various encephalopathies of toxic, septic, and metabolic origin.

 
A postmortem examination was conducted the day after her death and revealed congested, edematous lungs with multifocal areas of necrosis; marked vascular congestion with bilateral serous pleural effusions; hepatomegaly with microvesicular fatty change; renal tubular casts; and a normal heart. The pancreas did not show fat necrosis or fibrosis despite laboratory evidence of pancreatitis. There was no CE.

Multiple abnormalities were noted on neuropathology including pin-point hemorrhages (Fig 1C–F) in the hemispheric white matter and scattered throughout the brainstem and spinal cord. These petechial hemorrhages were characterized histologically by "ring-and-ball" morphology (Fig 1G), namely a blood vessel surrounded by an inner ring of red blood cells, fibrin, and inflammatory cells and an outer ring of pale myelin with no evidence of demyelination. Many of the neurones (Fig 1H) also had an appearance consistent with postmortem findings in the brains from patients with various encephalopathies of toxic, septic, and metabolic origin.15 No peripheral nerve abnormalities were seen, and the skeletal muscle was normal.

Patient2.
A 14-year-old previously well white girl presented to our pediatric emergency department with a 2-week history of polyuria, polydipsia, and a 2-kg weight loss. The night before, she had felt lethargic and went to bed early. Ten hours later, she was found unresponsive and dyspneic. On examination, her weight was 75 kg, height was 165.5 cm, BMI was 27.5 kg/m2, temperature was 37.1°C, blood pressure was 60/40 mmHg, heart rate was 103 beats per minute, respiratory rate was 34 breaths per minute, and GCS score was 3. She exhibited Kussmaul breathing, and her pupils were 4 mm bilaterally and weakly responsive to light. No evidence of trauma or illicit drug use was reported. She was intubated and ventilated. Fluids, inotropic support, and broad-spectrum antibiotics were given. Her initial blood glucose level was 34.8 mmol/L (685 mg/dL), and she was profoundly acidotic and ketotic (Table 1). Mannitol (75 g) was administered to treat suspected CE, although her CT brain scan was normal. A slow insulin infusion (0.03 U/kg per hour) was started to avoid rapid osmolar shifts.

Abnormal laboratory findings included low C-peptide levels (190 pmol/L, in response to the elevated blood glucose level of 20 mmol/L), elevated anti–glutamic acid decarboxylase antibodies (0.23 nmol/L [reference: <0.02 nmol/L]), and positive islet-cell antibody levels. Results of the remainder of the metabolic, vasculitic, and coagulation workups were negative, as were results from all bacterial and fungal cultures and polymerase chain reaction viral tests.

Her course in the hospital was complicated by acute renal failure and transient elevations in her lipase and pancreas-specific amylase level, which rose to twice the reference values before normalizing over 3 days. She remained comatose after correction of her metabolic acidosis and hemodynamic instability. Although there was no evidence of CE on imaging, an external ventricular drain (opening pressure was 14 cmH2O with a range of 12–18 cm [reference: <20 cm]) was placed to ensure normal intracranial pressure during correction of her hyperosmolar state. MRI of the brain showed no CE. There were, however, multiple well-defined hyperintense T2 foci associated with petechial hemorrhages involving the subcortical white matter U fibers bilaterally, genu of corpus callosum, and the posterior limb of the internal capsule bilaterally. There was a single focus of enhancement associated with a lesion in the left frontal lobe (Fig 2A and B). An angiogram showed numerous small segmental foci of decreased vessel caliber in the anterior and posterior circulations. On day 6 of admission, an MRI-guided left frontal craniotomy for brain biopsy was performed on the lesion in the left frontal lobe.


Figure 2
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  		FIGURE 2 Imaging and neurosurgical pathology findings (patient 2). A, Head MRI: single axial fluid-attenuated inversion recovery image demonstrating multiple well-defined foci of abnormal increased T2 signal scattered throughout both cerebral hemispheres involving predominantly the subcortical white matter. B, Single coronal multiplanar gradient recalled acquisition image. The arrows demonstrate punctate foci of abnormal diminished T2 signal associated with these lesions compatible with petechial hemorrhage. C, This low-power view of a gyrus (stained with hematoxylin, eosin, and Luxol fast blue) illustrates multiple small and microscopic hemorrhages (arrowheads) associated with "confluent" pallor (asterisks) of the myelin, a thin layer of preserved subcortical myelin (arrows), and normal cortex. D–F, These photomicrographs were taken from the same region; a vessel, labeled v, is identified for reference. In D, stained with Luxol fast blue, hematoxylin, and eosin (which stains myelin blue), the central hemorrhage was formed by perivascular necrosis (arrow), reminiscent of the lesions in patient 1, a concentric ring of red blood cells, and diffusely rarefied white matter that is speckled with eosinophilic astrocytes (arrowheads). Shown in E is a photomicrograph from a section treated with neurofilament immunohistochemistry (which labels axons dusky brown). Note the coarsening of axonal labeling in the center of the lesion, which indicates perivascular axonal injury (arrow), the loss (or separation) of axons in the red blood cell layer (asterisk), and the proportional labeling of axons compared with the myelin staining (illustrated in D). Shown in F is a photomicrograph of a section treated with CD68 immunohistochemistry (which labels microglia [rod-shaped or spindled cells] and histiocytes [round cells] brown). Note that there is no predilection of the activated/proliferating microglia/histiocytes for the perivascular lesions. Marked accumulation of these cells only occurred adjacent to, and in, the layer of preserved subcortical myelin. The pathological findings in case 2 are similar to those in case 1 with respect to the widely distributed small and microscopic hemorrhages. The hemorrhagic lesions differ between the cases in that, compared with case 1, the lesions are more numerous, their mantle of red cells is more prominent, the perilesional myelin pallor is confluent, and the microgliosis and astrocytosis is more prominent in case 2. The degree of gliosis in case 2 is likely to be a consequence of a longer interval between the onset of symptoms and pathological examination of the tissues. Note that in case 2 that the cortex, including the cortical neurones, was normal except for mild microgliosis.

 
The brain biopsy showed no abnormalities of the cortical neurons. There were extensive areas of petechial hemorrhage (Fig 2C) surrounded by pale white matter, with a ring-and-ball morphology (Fig 2D), with associated axonal injury but no evidence of demyelination (Fig 2E) or vasculitis (Fig 2F).

By day 10 of hospitalization, the patient demonstrated a slow improvement in her neurologic condition and no longer required ventilatory or inotropic support. In the initial phase of her convalescence, she had severe aphasia, very poor short-term memory, and motor apraxia, which were suggestive of diffuse frontal and temporal injury. She never exhibited focal motor or sensory findings. She was transferred to a brain rehabilitation unit and received intensive therapy over the next 2 months; she then was discharged from the hospital.

An MRI head scan was repeated 7 months after her initial presentation (data not shown). There was diffuse subcortical white matter volume loss. The magnetic resonance angiogram and venogram were normal. The patient has been followed in our pediatric diabetes and neurology outpatient clinics. There is no neurologic deficit on formal examination, but she has moderate cognitive deficits and short-term memory loss. She currently uses insulin glargine and aspart as part of a multiple daily-injection regime and maintains her hemoglobin A1c near 8.0%. She experiences occasional episodes of moderate hypoglycemia and has not had subsequent admissions to the hospital for DKA.

DISCUSSION

DKA is a common initial presentation of pediatric type 1 diabetes, with defined biochemical criteria including hyperglycemia, acidosis, and ketosis and incidences among newly diagnosed patients ranging from 15% to 67% in developed countries.16–18 Compared with adults, DKA in children carries higher morbidity and mortality largely because of intracerebral complications including CE and cerebrovascular accidents.19

The most common central nervous system complication of DKA in symptomatic children is CE, with major cerebrovascular insults comprising the remainder of the reported acute neurologic complications in children. Large subarachnoid hemorrhages have been described in 2 patients (aged 1 and 2 years), both of whom died6; in a radiographic series of 23 patients, 4 children showed evidence of subarachnoid or intraventricular hemorrhages and 3 had hemorrhages and CE.7 Intracerebral hematomas that occur with pediatric DKA have been described in a 10-year-old girl with bitemporal posterior intracerebral hematomas12 and in a 15-year-old girl with focal neurologic signs and multiple cerebral hematomas localized to the parietoocciptal region.10 Children with DKA have also been described with stroke and brain infarction.7,11,12 These major cerebrovascular events likely relate to a hypercoagulable state, which occurs with diabetes.20

In our report, neither patient had impaired coagulation study results or neuroimaging or angiographic changes to indicate major cerebrovascular disease. Both patients presented in a coma that resolved in the surviving patient with no focal neurologic deficits. CE was not present in either of our patients on neuroimaging, direct intracranial pressure monitoring in patient 2, or on gross or microscopic specimens taken. Medical therapy, including mannitol, would not have completely reversed any CE that may have been present.

Patients who present with severe DKA have been shown to undergo significant metabolic, inflammatory, and oxidative stresses consistent with a noninfectious SIR. The SIR has been shown by elevated levels of proinflammatory cytokines including interleukins 6 and 1β and C-reactive protein,21–23 in addition to the generation of reactive oxygen species and reduced levels of antioxidants.24,25 Other markers of the inflammatory cascade include complement activation, which has been demonstrated on neurons, oligodendrocytes, and blood vessels of adolescents who died as a result of CE in DKA.26,27 The cerebral microvasculature in DKA is further modulated by circulating ketones, β-hydroxybutyrate, and acetoacetate, which alter the permeability of endothelial cells in vitro.28,29 Pediatric brains also take up and utilize ketones at a four- to fivefold faster rate than adults, and ketones accumulate in the brain of pediatric patients with DKA.30,31 These features, coupled with larger brain volumes, less developed osmoregulatory pathways, and more porous blood-brain barriers, may also explain why children who present with DKA are at increased risk of intracerebral crises.32,33

Although MRI studies in children with diabetes have not reported white matter changes similar to those described in this report, hyperintense T2 white matter lesions are well recognized in adults with cerebrovascular disease, hypertension, and/or diabetes and in older healthy people as part of the aging process.34–37 Diffuse white matter hemorrhages occur in response to localized endothelial cell injury, usually secondary to localized hypoxia and ischemia, with or without thrombocytopenia, in conditions such as disseminated intravascular coagulopathy, thrombotic thrombocytopenic purpura, and air and fat emboli.38 Acute lead poisoning in children and cerebral malaria are other causes.39,40 The petechial hemorrhages detailed in this report occurred in the absence of coagulopathy or embolic disease and suggest disruption of the small white matter vessels, presumably related to a cytotoxic process. An analogous process has been proposed to explain the pathogenesis of "septic encephalopathy," in which a systemic process, in this case mediated by endotoxin, results in an SIR in combination with endothelial injury, ischemia, and breakdown of the blood-brain barrier.41–43 For the cases described in this report, the presence of perivascular axonal injury, rhabdomyolysis, and pulmonary edema favors the operation of cytotoxic factors (separately or in combination) that are peculiar to events associated with the acute onset of DKA in children. These factors include poor perfusion, acidosis, hyperglycemia, and ketonemia, and their clinical and pathologic manifestations will vary depending on the timing, extent, and particular combination of cytotoxic events. This phenomenon has been described in pediatric DKA, with capillary disruption producing facial and peripheral edema observed in the absence of CE,44 CE without pulmonary edema,6,8 and, like in our first patient, acute pulmonary edema without evidence of cerebral findings.45,46 It remains unclear why, faced with similar cytotoxic factors, some patients' conditions progress to CE and others do not.

Although we propose that these lesions resulted from cytotoxic factors related to metabolic abnormalities and the SIR, alternative etiologies require consideration. These white matter lesions are unlikely to have been a preexisting condition, because white matter abnormalities are not commonly seen in normal children and adolescents.34 An atypical form of disseminated intravascular coagulopathy is a possibility, in which tests of coagulation do not coincide with the hematologic insult; however, there was no evidence of microthrombi, fibrinoid necrosis, or vasculitis seen on microscopy in either case. Although we cannot exclude shock secondary to an inflammatory state (ie, viral sepsis) leading independently to endothelial dysfunction in cerebral vessels, this seems unlikely, because pathology results for both patients was not consistent with hypoperfusion and infarction. Furthermore, we did not observe microscopic, ischemic changes in hippocampal neurons (red, pink coloration), which present as part of the hypoxic-ischemic encephalopathy of septic shock. Both patients presented with hypotension, but distal perfusion was unlikely to be significantly compromised because the lactate levels on admission were within the reference range, which indicates adequate oxygen delivery. Thus, the specific brain pathologic findings and coma observed in our patients is likely related directly to development of DKA, perhaps combined with other unidentified risk factors.

The cases described in this report contribute new pathologic information to our understanding of DKA in children. The pathologic findings in both cases were similar with respect to the widely distributed small and microscopic hemorrhages. The hemorrhagic lesions differed between the cases in that, compared with case 1, the lesions were more numerous, the mantle of red cells was more prominent, and the perilesional myelin pallor was confluent in case 2. The extent of hemorrhages between patients may have related also to the timing of presentation, level of acidosis, ethnicity, and/or differences in BMI. Although both patients met criteria for DKA, our first patient had multiple risk factors for type 2 diabetes, including aboriginal ancestry and elevated BMI. Indeed, type 2 diabetes was demonstrated recently to cause DKA in a significant number of presenting adolescent cases.47 The first case presented here also shares similarities with the previously reported case of a black 16-year-old boy with a BMI of 33.8 kg/m2, hypotension, and rhabdomyolysis who died as a result of renal failure and was reported to present with hyperglycemic hyperosmolar coma.47 Our patient had profound acidosis at presentation, a lower initial blood glucose level, and significant ketonemia, which are more consistent with DKA than hyperglycemic hyperosmolar coma, although mixed presentations can occur.47,48 In the second patient, we were careful to optimize fluids with inotropic support and initiate insulin as a slow infusion. In addition, the second patient had intracranial pressure measurements to monitor the effects of the slow osmolar correction.

CONCLUSIONS

We have described 2 cases of diffuse white matter focal hemorrhages that may have been caused by a diabetic small vessel injury, possibly caused by circulating cytotoxic factors. Physicians who care for children should be aware that hyperglycemic coma in adolescents is not only associated with CE. These cases provide further clinical and neuropathologic insight into the cerebral dysfunction present in children with severe DKA.

ACKNOWLEDGMENTS

Dr Fraser is supported by the Children's Health Research Institute and the Centre for Critical Illness Research and is a strategic training fellow of the Canadian Institutes of Health Research in the Canadian Child Health Clinician Scientist Program.

FOOTNOTES

Accepted May 17, 2007.

Address correspondence to Farid H. Mahmud, MD, Division of Pediatric Endocrinology, Children's Hospital of Western Ontario, 800 Commissioners Rd E, London, Ontario, Canada N6C 2V5. E-mail: farid.mahmud{at}lhsc.on.ca

The authors have indicated they have no financial relationships relevant to this article to disclose.

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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