CASE REPORT Open Access

Metabolic encephalopathy secondary todiabetic ketoacidosis: a case reportMaria Tomkins1* , Richard McCormack2, Karen O’Connell3, Amar Agha4 and Áine Merwick3

Abstract

Introduction: Metabolic encephalopathy is a rare but potentially devastating complication of diabetic ketoacidosis(DKA). This case highlights the dramatic cognitive decline of a young man due to metabolic encephalopathycomplicating DKA. The aims of this case report are to highlight metabolic encephalopathy as a complication ofDKA and to explore the current research in diabetic related brain injury. The importance of investigation andtreatment of reversible causes of encephalopathy is also demonstrated.

Case presentation: A 35-year-old man with a background of type 1 diabetes mellitus (T1DM) and relapsing remittingmultiple sclerosis (RRMS) presented to the emergency department (ED) in a confused and agitated state. Prior to admission heworked as a caretaker in a school, smoked ten cigarettes per day, took excess alcohol and smoked cannabis twice per week.Following initial investigations, he was found to be in DKA. Despite timely and appropriate management his neurologicalsymptoms and behavioural disturbance persisted. Neuroimaging revealed temporal lobe abnormalities consistent with anencephalopathic process. The patient underwent extensive investigation looking for evidence of autoimmune, infective,metabolic, toxic and paraneoplastic encephalopathy, with no obvious cause demonstrated.Due to persistent radiological abnormalities a temporal lobe biopsy was performed which showed marked astrocytic gliosiswithout evidence of vasculitis, inflammation, infarction or neoplasia. A diagnosis of metabolic encephalopathy secondary toDKA was reached. The patient’s cognitive function remained impaired up to 18months post presentation and he ultimatelyrequired residential care.

Conclusions: Metabolic encephalopathy has been associated with acute insults such as DKA, but importantly, the risk ofcerebral injury is also related to chronic hyperglycaemia. Mechanisms of cerebral injury in diabetes mellitus continue to beinvestigated. DKA poses a serious and significant neurological risk to patients with diabetes mellitus. To our knowledge this isthe second case report describing this acute complication.

Keywords: Diabetes mellitus, Metabolic encephalopathy, Ketoacidosis, Diabetic brain injury, Type 1 diabetes

BackgroundDiabetic ketoacidosis is a frequent complication of type 1diabetes, with the UK National Diabetes Audit quoting acrude incidence rate of 3.6% among patients with type 1diabetes [1]. Risk factors for DKA include younger age,poor glycaemic control, lower socioeconomic status anddepression/psychiatric illness. Precipitants of DKA includeomission of or inadequate insulin, infection, cardiovasculardisease such as stroke/acute coronary syndrome, acute pan-creatitis and certain medications such as steroids, thiazidediuretics and sodium-glucose-co-transporter 2 (SGLT2)

inhibitors. Physiological stress from surgery, pregnancy ortrauma has the potential to initiate a DKA due to increasedrelease of counter-regulatory hormones [1].Metabolic encephalopathy refers to an alteration in con-

sciousness due to impaired cerebral metabolism causing dif-fuse or global brain dysfunction in the absence of primarystructural dysfunction [2]. Chemical imbalance occurs in thesetting of hypoxia or due to systemic organ failure (hepaticfailure, renal failure, pancreatic failure) and electrolyte imbal-ance (hypercalcaemia, hypoglycaemia, hyponatraemia) result-ing in toxic neurological injury [2]. Varying presentationsoccur and may indicate the underlying cause, for examplepatients with hepatic encephalopathy may demonstrateasterixis, however in general metabolic encephalopathy pre-sents as global cerebral dysfunction with fluctuating

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

* Correspondence: mariatomkins200@gmail.com1Department of Diabetes and Endocrinology, Beaumont Hospital, Dublin,IrelandFull list of author information is available at the end of the article

Tomkins et al. BMC Endocrine Disorders (2019) 19:71 https://doi.org/10.1186/s12902-019-0398-8

consciousness in the absence of focal neurological signs [3,4]. It is a very rare but potentially devastating complicationof diabetic ketoacidosis (DKA). Hitherto, only one case hasbeen reported of this complication in which the patientshowed a gradual recovery with residual speech disturbanceand irritability [5].In this paper we describe a case of a patient with persist-

ing neurological injury secondary to metabolic encephal-opathy associated with DKA. The aims of this case reportare to highlight metabolic encephalopathy as a complica-tion of DKA and to explore the current research in dia-betic related brain injury. The importance of investigationand treatment of reversible causes of encephalopathy isalso demonstrated, as this is a diagnosis of exclusion.

Case presentationA 35-year-old man with T1DM presented to ED, havingbeen found in an acutely confused state at home. Having notleft his bedroom for 2 days, his co-habitants alerted emer-gency services who forced entry to his bedroom and foundhim in an unkempt, confused state. On arrival he was agi-tated, confused, unkempt and uncommunicative. The major-ity of the clinical history was provided by his parents whohad seen him well 2 days previously. They described an inde-pendent 35-year-old man who had no complaints in the daysleading up to his admission. They described poor engage-ment with medical services regarding his diabetes and mul-tiple sclerosis. His social and recreational history wasprovided by the family, who were aware of his occasionalillicit drug use, excessive alcohol intake and smoking status.Additional information regarding his past medical interven-tions and treatments was available in his medical record.His medical background was significant for T1DM, diag-

nosed at age nine. He was taking basal/bolus insulin. Hisdiabetes was complicated by background diabetic retinop-athy. He poorly engaged with diabetes services and had notattended his diabetes clinic appointments for two yearsprior to presentation, solely attending his general practi-tioner when repeat insulin prescriptions were required. Hehad a history of poor glycaemic control with HbA1c ran-ging from 67 to 99mmol/mol (8.3 to 11.2%) over the previ-ous ten years, one previous DKA eleven years prior whichwas attributed to excess alcohol intake and omission of in-sulin and one previous hypoglycaemic seizure following in-correct self-administration of insulin. Relapsing RemittingMultiple Sclerosis (RRMS) was diagnosed at age 26, and hewas an infrequent attender of the neurology clinic, havingpreviously been prescribed interferon beta but had self-discontinued using 5 years previous. His multiple sclerosishad been clinically and radiographically stable; with mostrecent MRI brain performed 2months prior to his presen-tation (Fig. 1). He had been suffering with mild to moderatedepression for four years prior to admission and was takingescitalopram. He also had experienced a suspected seizure

six months prior to his presentation however, unfortu-nately, he failed to attend for investigation of this episode.There was no significant family history. He worked as a

caretaker in a school, was living independently andsmoked ten cigarettes per day. He also was known to takeexcess alcohol, and smoked cannabis twice per week.On examination his vital signs were normal however his

Glasgow Coma Scale (GCS) was 9 (eye opening 3, verbal re-sponse 1, motor response 5). Cardiovascular, respiratory andabdominal exams were normal. Focused neurological exam-ination including cranial nerves, fundoscopy, gait, tone andreflexes did not show a focal deficit but was limited especiallyin higher cortical function assessment by inability of the pa-tient to co-operate with examination.

InvestigationsBiochemistry was consistent with DKA (pH 7.17, blood ke-tones 8mmol/L and blood glucose 26mmol/L). Alcohollevels were undetectable, urine and serum toxicologyscreens were negative and there was no clinical, biochem-ical or radiological evidence of infection. Full blood count,urea and electrolytes, liver function, and C-reactive proteinwere normal. Thyroid function, iron, ferritin and B12 werenormal, however he was folate deficient (2.3μg/L). HbA1cwas 70mmol/mol (8.5%). Computed tomography (CT) im-aging of the brain showed no acute pathology.Cerebrospinal fluid (CSF) analysis on the second day of ad-

mission revealed an elevated protein at 61mg/dl with nor-mal glucose 6.3mol/L, erythrocytes 86u/L and leucocytes 1/uL. CSF Viral PCR for Herpes Simplex Virus 1 + 2, VaricellaZoster Virus, Enterovirus, Human Herpes Virus 6, EpsteinBarr Virus DNA, John Cunningham Virus (JCV) DNA andcytomegalovirus were all negative. CSF cytology showed noevidence of abnormal or malignant cells. Serum and CSFgram stain and culture were both negative. Serum Trepo-nema pallidum, HBV, HCV and HIV 1+ 2 were negative.Connective tissue disease screen including antibodies to

anti-nuclear factor, double stranded DNA, RNP, anti-phospholipid, Smith, Ro and La were all negative. Beta-2glycoprotein and anticardiolipin IgG and IgM were normal.Immunoglobulins G, A and M and serum protein electro-phoresis were normal.Serum paraneoplastic antibodies were negative. Extensive

immunological screen of anti-GFAP, anti =GAD65, anti-MOG, anti-GABAB receptor, anti-AMPA I+ II, Aquaporin 4NMO, Anti TTG antibodies were negative. Immunofluores-cence and immunoblot did not reveal evidence of Anti-Yo,Anti-Hu, Anti- Ri, Anti Ma1, Anti Ma2, anti-cv2/CRMP5,Amphiphysin, Sox-1, Zic-4, anti-Tr antibodies. Anti-VGKC,anti-NMDA receptor and anti-TPO antibodies were negative.Carnitine, homocysteine, vitamin D and ammonia levels werenormal. Mitochondrial POLG genetics were negative. Anti-glutamic acid decarboxylase levels were negative/within nor-mal range.

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An Electroencephalogram (EEG) was attempted repeat-edly, but unfortunately was abandoned on a number ofoccasions, due to severe agitation. When obtained threeweeks after presentation, EEG showed global cerebral dys-function without definite epileptiform features and noelectroencephalographic seizures were detected.MRI brain scan showed new diffuse high signal changes in

both temporal lobes and hippocampi (Fig. 1c-f). He also had anumber of subcortical and periventricular demyelinating pla-ques, that were stable in number and size compared with his

most recent RRMS surveillance MRI (Fig. 1a-b). Follow-upimaging at 6weeks showed progression of these changes withhigh signal now extending into the insular cortex bilaterally.Due to these progressive radiological changes and lack

of clinical improvement the patient underwent atemporal lobe biopsy which showed marked astrocyticgliosis, without evidence of vasculitis, diffuse parenchy-mal inflammation, infarction or neoplasia (Fig. 2a-b).Immunostaining for HSV1, HSV2 and SV40 (JCVmarker) were all negative.

Fig. 1 Axial FLAIR (a) and saggital FLAIR (b) sequences from last surveillance MRI for his MS taken 2 months prior to presentation shows stableperiventricular white matter lesions with evidence of an isolated demyelinating plaque in his right temporal horn. Axial FLAIR (c and d) sequenceat presentation shows high signal abnormality in both temporal lobes extending to the insular cortex. Axial diffusion weighted imaging (e) showsno restricted diffusion and susceptibility weighted imaging (f) shows no area of focal haemorrhage

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Timeline

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Differential diagnosisThe precipitant of DKA in this case is unclear givenhis absent period prior to admission, and may havebeen multifactorial. We postulate that it may be dueto a combination of omission of insulin with or with-out alcohol misuse, as this was his previous precipi-tant. Starvation and alcohol excess may have alsocontributed to ketoacidosis.There are multiple differentials of encephalopathy in

this case. As the patient was not seen for two daysprior to presentation he may have had an unwit-nessed traumatic brain injury however this was notapparent on imaging. Toxic brain injury was alsoconsidered however the radiological findings wereinconsistent with this and toxicology screen was nega-tive. Wernicke’s encephalopathy was considered givenhis previous alcohol history, however there was noimprovement with high dose B vitamin supplementa-tion and the clinical and imaging features would notbe in keeping with that diagnosis. Infectious aetiologyshould always be considered in patients presentingwith encephalopathy. Indeed, the finding of high sig-nal within the temporal lobes extending to the insulawould fit with a viral encephalitis, such as that causedby HSV. However, the lack of diffusion restrictionand microhaemorrhages on his imaging, lack of brainbiopsy features as well as repeatedly negative CSFviral PCR and normal leucocyte count make this diag-nosis unlikely. Other rarer causes of encephalopathyincluding autoimmune, vasculitic and paraneoplasticdisease were also explored and ruled out. Sub-clinicalseizure activity may have caused his persistent behav-ioural disturbance in the acute phase but unfortu-nately the patient was initially unable to cooperatewith EEG testing and there were no features on re-peated clinical examination by a neurologist of overtseizures. Nutritional deficiency such B vitamin / folatedeficiency could have also played a role, the patienthad mild folate deficiency which would not typicallycause such a devastating neurological injury, howevermay have contributed to susceptibility to brain injury.Cerebral oedema due to diabetic encephalopathy can

cause brain injury however there was no clinical orradiographical evidence of this. Therefore, we feel thatmetabolic encephalopathy due to DKA is the most likelydiagnosis in this case.The differential of metabolic encephalopathy second-

ary to DKA was raised approximately one week into theclinical admission following negative viral PCR and lackof improvement with thiamine and chlordiazepoxide.Initially the most likely diagnosis was a viral or toxicencephalopathy, however with no clinical improvementto treatment a wider differential was considered. Acomprehensive suite of investigations ensued to

undercover the aetiology of the patient’s behaviouraldisturbance, however neither imaging, laboratory orpathological specimens led to a definite cause. Follow-ing multidisciplinary discussion, the diagnosis of meta-bolic encephalopathy secondary to DKA was reached.

Treatment and clinical courseHe was commenced on a DKA management protocolwhich consisted of aggressive intravenous fluid resus-citation, intravenous continuous insulin infusion andintravenous and oral replacement of potassium, phos-phate and magnesium. DKA management protocolwas continued for forty-eight hours, at which pointall biochemical markers were within normal limitsand the patient was transitioned to basal-bolus insulinregimen. In addition, the patient was also given intra-venous high dose B vitamins and a reducing regimenof chlordiazepoxide over one week. He received folicacid supplementation 5 mg daily for two months. Sub-sequent treatment was largely supportive. Empiricantiviral therapy was given for HSV (later HSV PCRcame back as negative, although two-week coursecomplete). He underwent intensive rehabilitation in-volving a multidisciplinary team of occupational ther-apy, physiotherapy, social care and neuropsychology.Subsequent imaging at 3, 4 and 6months post presen-

tation demonstrated persistent but stable high-signalchanges in the temporal lobes bilaterally.Unfortunately following temporal lobe biopsy the pa-

tient experienced generalized tonic clonic seizures whichwere difficult to control, requiring three antiepilepticagents. EEG was performed at this point, ten weeks intohis admission following temporal lobe biopsy. The find-ings were in keeping with an encephalopathic state witha highly epileptogenic focus in the left frontocentralregion.He remained relatively unchanged for the next 18

months with persistent severe global cognitive impair-ment with most marked deficits in attention, short-term memory and ability to learn new information.He had ongoing erratic control of his blood sugars,attributable to inconsistent oral intake. He continuedto have seizures with generalised tonic-clonic eventsoccurring approximately once per month. Behaviouralissues remained a problem and he required constantsupervision, ultimately requiring long term residentialcare.

Discussion and conclusionsRegarding the strengths of this case report, it is clearthat the patient was extensively investigated to ensurepossible reversible causes were outruled. Limitations ofthis case report include the lack of EEG in the acutephase due to patient agitation.

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From review of the literature, brain injury as a resultof DKA has been well described in the paediatric popu-lation however the mechanisms of brain injury remainunclear. This uncertainty is mostly due to the myriad ofmetabolic disturbances which occur during DKA [6].There is a paucity of cases describing metabolic enceph-alopathy secondary to DKA in the adult population.Miras et al. described a very similar case in a 44 year oldman [5]. Similarly, he was found collapsed and had notbeen contactable for 3 days prior to his admission. Inter-estingly, he also had a history of alcohol excess andpoorly controlled type 1 diabetes with recurrent severehypoglycaemic episodes. In this case the patient had sig-nificant behavioural disturbance with aggression andconfusion. Neuroimaging was entirely normal, CSFexamination was bland and EEG showed diffuse slowingconsistent with encephalopathy. Over the following sixmonths this patient gradually improved with neuro-psychiatric rehabilitation however had residual irritabil-ity and slow speech [5].DKA has been shown to induce brain injury how-

ever the exact pathogenesis of this injury is debated.In paediatric cases subclinical cerebral oedema iscommon, with frank cerebral oedema occurring in0.5–1% of children with DKA [7]. Historically cerebraloedema secondary to DKA was thought to be due tooveraggressive fluid resuscitation and loss of brain os-motic homeostasis, however recently this theory hasbeen challenged. Cerebral hypoperfusion followed byreperfusion injury correlates with the spectrum ofcytotoxic and vasogenic oedema seen in patients withcerebral oedema due to DKA and is now hypothe-sized to be the mechanism of brain injury in DKA[7]. However, cerebral oedema in the setting of DKAor Hyperglycaemic hyperosmolar syndrome (HHS) inadults is exceedingly rare, with a United States large

population-based study revealing a 0.03% incidencerate [8]. In the case outlined above there was no evi-dence of cerebral oedema clinically or radiologically,therefore other mechanisms of brain injury must beat play.Interestingly Jessup et al., studied a cohort of young

patients with new onset type 1 diabetes and foundthat patients who presented with DKA scored loweron visual cognitive tasks when compared to age-matched patients without DKA. Cognitive disparitybetween the two groups remained 8–12 weeks postdischarge. The authors suggest that metabolic dysreg-ulation during DKA mediates neuroinflammation andcerebral oxidative stress causing a neuronal injury [9].This is further supported histologically, where exam-ination of brain tissue from patients with DKA andcerebral oedema showed evidence of oxidative stress,with increased products of oxidative damage presentin vulnerable brain areas compared to healthy con-trols [10]. Hoffman et al., also showed that both acuteand chronic metabolic dysregulation in T1DM canaffect brain function, promoting neuroinflammation,cerebral insulin resistance and reduced insulin signal-ling, culminating in increased oxidative and inflamma-tory cerebral stress [10]. Chronic hyperglycaemia,ketoacidosis and dehydration with superimposed acuteinsults, in the form of DKA, can subsequently causediabetic encephalopathy [10]. The long-term erraticglycaemic control in the case outlined above maytherefore have also played a role in the patient’s cog-nitive decline.Recent research has indeed demonstrated chronic

altered brain metabolism and signalling as a cause ofdiabetic brain dysfunction. Analysing brain metabo-lites with magnetic resonance spectroscopy (MRS)reveals significant alterations in levels of brain

a b

Fig. 2 Astrocytic gliosis. (a) H&E and (b) glial fibrillary acid protein (GFAP) stained sections demonstrate marked astrocytic gliosis characterised byan evenly dispersed proliferation of large reactive astrocytes with abundant eosinophilic cytoplasm and branching processes (arrows)

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metabolites in the diabetic brain, which are consistentwith and related to specific diabetic complications.Changes in these metabolites has been hypothesizedto cause reduced neurotransmission, demyelination,neurodegeneration and brain atrophy. The study ofbrain metabolites and use of MRS in diabetic braindisease is at the initial stages. Further research anddevelopment could unveil the exact mechanism ofdiabetic brain injury as well as provide a new diag-nostic tool to evaluate early disease and allow inter-vention [11].In the case outlined above there are also nutritional

factors which may have increased the risk of brain in-jury. Folic acid deficiency has been linked to cognitiveimpairment with behavioural disturbance in youngadults [12]. Non-ketotic hyperglycaemia (NKH) canresult in multiple neurological consequences such asseizures, hemichorea and hemianopia. In NKH,hyperglycaemia-induced blood brain barrier perme-ability contributes to epileptogenesis [13]. Therefore,we may hypothesize that recurrent hyperglycaemiaand subsequent blood brain barrier permeability mayhave contributed to epileptogenesis and indeed braininjury in this case. Moreover, multiple sclerosis re-lated blood-brain barrier permeability, although notthe primary pathology in MS, may have contributedto reduced neuroprotection and increased risk of en-cephalopathy [14]. Factors such as nutritional defi-ciency, alcohol excess, cannabis use, depression andmultiple sclerosis may have contributed to this pa-tient’s susceptibility to encephalopathy however meta-bolic encephalopathy secondary to diabeticketoacidosis was the most likely diagnosis.In summary, metabolic encephalopathy is a devastat-

ing complication of DKA which can be due to bothacute and chronic metabolic brain insults. To our know-ledge this is the second case report describing this acutecomplication. It is an area of expanding research whichwill hopefully lead to improved understanding, treat-ment and patient outcome.

AbbreviationsAMPA: Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;CSF: Cerebrospinal fluid; DKA: Diabetic Ketoacidosis; DNA: Deoxyribonucleicacid; ED: Emergency Department; EEG: Electroencephalogram; FLAIR: Fluid-attenuated inversion recovery; GABA: Gamma-aminobutyric acid;GAD: Glutamate acid decarboxylase; GCS: Glasgow Coma Scale; GFAP: Glialfibrillary acidic protein; H&E: Haematoxylin and eosin; HbA1c: HaemoglobinA1c; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HHS: HyperglycaemicHyperosmolar Syndrome; HIV: Human Immunodeficiency Virus; HSV: HerpesSimplex Virus; IgG: Immunoglobulin G; IgM: Immunoglobulin M; MOG: MyelinOligodendrocyte Glycoprotein; MRI: Magnetic Resonance Imaging;MRS: Magnetic resonance spectroscopy; NKH: Non-ketotic hyperglycaemia;NMDA: N-methyl-D-aspartate; NMO: Neuromyelitis optica; PCR: PolymeraseChain Reaction; POLG: DNA polymerase subunit gamma; RNP: Ribonuclearprotein; RRMS: Relapsing Remitting Multiple Sclerosis; SGLT2: Sodium-Glucose-Co-Transporter 2; T1DM: Type 1 diabetes mellitus; TPO: Thyroid

peroxidise; TTG: Tissue Transglutaminase; VGKC: Voltage gated potassiumchannel

AcknowledgementsDr. Alan Beausang Consultant Neuropathologist, Beaumont Hospital, Dublin,Ireland and Dr. Paul Brennan Consultant Neuroradiologist, BeaumontHospital, Dublin, Ireland and Dr. Gerard Mullins Consultant Neurophysiologist,Beaumont Hospital, Dublin, Ireland.

Authors’ contributionsMT: primary author, contributed to conception, preparation and editing ofreport. RMC contributed to manuscript conception, reviewed and addedradiology findings. KOC contributed to manuscript editing and addedpathology findings. AA and AM: senior authors, contributed to manuscriptconception and editing. All authors reviewed and approved the manuscript.

FundingNo funding was received for this study.

Availability of data and materialsNone of the raw data pertaining to this case report is available publicly. Theoriginal investigation findings and reports are retained, as per normalprocedure within the medical records of our institution.

Ethics approval and consent to participateNot applicable.

Consent for publicationWritten informed consent to publish the patient’s personal data wasobtained from the patient’s next of kin and family. A copy of written consentis available for review by the Editor of this journal.This manuscript was developed with adherence to the CARE guidelines andmethodology.

Competing interestsAmar Agha is a member of the editorial board (Section Editor) of BMCEndocrine Disorders. All other authors declare that they have no competinginterests.

Author details1Department of Diabetes and Endocrinology, Beaumont Hospital, Dublin,Ireland. 2Department of Rehabilitation, National Rehabilitation Hospital,Dublin, Ireland. 3Department of Neurology, Beaumont Hospital, Dublin,Ireland. 4Department of Diabetes and Endocrinology, Beaumont Hospital,Dublin, Ireland.

Received: 23 January 2019 Accepted: 12 June 2019

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