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Hypoglycaemic events can resemble focal seizures semiologically.
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Confirming the diagnosis by video EEG is important in drug resistant epilepsy.
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Insulinomas can lead to a misdiagnosis of epilepsy.
Abstract
Purpose
To review the literature, for cases of hypoglycaemia misdiagnosed as epilepsy, including our interesting case of a patient with Type 1 Diabetes Mellitus, diagnosed with focal epilepsy.
Methods
A literature search was completed. 20 of 473 studies, with a total of 22 cases found using specified search terms were relevant to this review. The papers identified and reviewed were those that dealt with hypoglycaemia misdiagnosed as epilepsy. The majority are isolated case reports given the rarity of this entity.
Results
An underlying insulinoma is the most common cause for hypoglycaemic episodes to be misdiagnosed as epilepsy. Early morning seizures were prominent in 9 of the 22 cases.
Conclusion
Although rare, hypoglycaemia is an important differential diagnosis for drug-resistant epilepsy and early morning events may be an indication. We report the first case of recurrent hypoglycaemia from exogenous insulin, misdiagnosed as focal epilepsy with an available video EEG. The unusual presentation appeared clinically indistinct from recurrent focal seizures.
Hypoglycaemia is associated with several neuroglycopenic symptoms and signs, that result from direct central nervous system deprivation of glucose. These include behavioural changes, confusion, fatigue, and seizures. Generalised hypoglycaemic seizures present on electroencephalogram [EEG] as diffuse slowing in the delta and theta range. [
We report our unique case, as well as a comprehensive literature review, focusing on cases of hypoglycaemia misdiagnosed as epilepsy. The literature review aimed to improve awareness of the manifestations of hypoglycaemia, especially those that can mimic epileptic seizures.
This case highlights the risk of misdiagnosis of epilepsy in hypoglycaemia-driven cerebral dysfunction and subsequent exposure to inappropriate anti-epileptic therapy. It also reiterates the value of continuous video-EEG monitoring in determining the nature and aetiology of seizure activity.
2. Case study
2.1 Clinical history
A 42-year-old right-handed fisherman with a 34-year history of type 1 diabetes mellitus, was referred to the National Centre of Epilepsy as a case of refractory focal epilepsy. Hisdiabetes was complicated by peripheral neuropathy, nephropathy, and retinopathy. Comorbidities included hypertension, dyslipidaemia, hypothyroidism, and depression. He was treated with a basal-bolus insulin regime of insulin glargine 20 units at night, and insulin apart 3–9 units before meals, once-daily acetylsalicylic acid 75 mg, atorvastatin 20 mg, ramipril 10 mg, verapamil 120 mg and l-thyroxine 100 µg.
He had no early life risk factors for epilepsy. He did however have an extensive history of recreational drug abuse and heavy alcohol intake. Our patient reported a history of possible viral encephalitis, with a 10-weeks admission to a regional general hospital 10 years previously. However, in our assessment of the case, we were unable to find radiological or microbiological evidence to support this diagnosis.
The first reported seizure occurred in August 2010. While on his fishing boat, he became confused and aggressive towards his colleagues. They reported that he developed a blank facial expression and exhibited a reduced level of responsiveness. The patient himself did not have any recollection of the event. He described being extremely tired and slightly confused afterwards. Of note, he did not eat or drink anything, or receive glucagon before recovering from the event. He was admitted to a general hospital and underwent extensive neurological investigation including brain magnetic resonance imaging and neurophysiological studies, which were normal. He received a clinical diagnosis of focal epilepsy and began anti-epileptic therapy.
Following this initial presentation, the patient continued having recurrent episodes of agitation, impaired awareness and confusion. His family repeatedly reported that he developed a blank facial expression and associated oral automatisms. Interestingly, the patient has never reported warning symptoms. Typically, these episodes would last for a few minutes, occurring two to three times a week on average. On rare occasions, they could last up to two hours. Post-ictally, he reported headache, right-sided hemiparesis, expressive dysphasia and amnesia, as well as fatigue lasting for up to twenty-four hours after the event. His treating physicians continued to manage these episodes with increasing numbers of anti-epileptic medications. By the time the patient was referred to the National Centre of Epilepsy as a case of refractory focal epilepsy, he was taking Levetiracetam 1000 mg BD and Lamotrigine 100 mg BD. He had been on Carbamazepine and Sodium Valproate in the past as well which were stopped due to ineffectiveness.
The patient was admitted to the Epilepsy Monitoring Unit to clarify whether these events were epileptic in nature and if so, to determine the possibility of epilepsy surgery. The patient's physical and neurological examinations were normal. His-HbA1c was 7.2%, while it had been 15% five years prior. A neurophysiological study by continuous video-EEG monitoring was performed for 21 days.
2.2 Video EEG
Interictal EEG showed an excess of intermittent bilateral temporal slowing in the theta range (5–7 Hz) during wakefulness, with rare bihemispheric sharp waves over both frontotemporal regions in the awake and sleep states, in keeping with non-specific bihemispheric dysfunction. During this admission, two clinical episodes were captured.
The first episode occurred on the eleventh day of admission. It was subtle and only reported by the patient a day later when he described a period of amnesia during the previous evening. Objectively he appeared withdrawn and drowsy for 1 hour and 45 min. The EEG recording during this period showed diffuse slowing with excess theta and delta activity compared to baseline. There was bihemispheric 5–7 Hz theta slowing of up to 80uV in amplitude, progressing to bilateral 3–4 Hz delta activity. As the episode progressed, this background generalised slowing was intermixed with bihemispheric sharp waves, occurring maximally over the right temporal region but also occurring independently over the left temporal region, reaching amplitudes of 130Uv. The blood glucose level at this time was 2.1 mmol/l. The EEG normalised following food consumption.
The second event occurred on the fifteenth day of admission. Objectively, he became unresponsive and clammy. He was disorientated in place and unable to follow commands. This was followed by confusion and bizarre speech, repeatedly calling out inappropriate phrases such as "chicken out of the bed" and "chicken at the window." Subtle oral automatisms were observed. The event was fifteen minutes in duration. During this period, the EEG again showed progression from theta to delta bihemispheric slowing, with the 2–4 Hz activity of up to 105uV in amplitude, with intermixed bihemispheric frontal-maximal sharp complexes. As the slowing enhanced, bi-hemispheric frontal-predominant periodic sharp and slow wave complexes occurred, in keeping with an evolving severe metabolic encephalopathy. His-blood glucose at this time was 1.1 mmol/l. He was given a glucose drink and the disturbance resolved, with normalisation of the EEG record six minutes after ingestion.
The EEG recordings during these events showed generalised slowing, with concomitant low blood glucose measurements demonstrating that these events were the result of a metabolic encephalopathy driven by hypoglycaemia. Following the conclusion of this study, the diagnosis of epilepsy was revised and all anti-epileptic medications were stopped.He was referred to endocrinology and underwent insulin pump and continuous glucose sensor insertion. To the best of our knowledge, he has not had any further clinical events over the last 6 years.
3. Literature review
3.1 Methods
A literature search was carried out using the search terms: hypoglycaemia, insulinoma, electroencephalography, seizure, epilepsy, anticonvulsant. Medline and Embase databases were searched. Controlled vocabulary, both MeSH terms and Emtree terms were used. Boolean operators; ((hypoglycaemia) OR (insulinoma) AND (EEG) AND ((seizure) OR (epilepsy) OR (anticonvulsants)) limited results to cases that included an EEG. This yielded 473 articles that were in English [568 total]. The search was performed on 20/01/2021.
Date limits applied 01/01/1980- 20/01/2021. References of relevant papers were screened for further potentially relevant case reports. Studies ruled out included those in which hypoglycaemia, especially in the neonatal period had resulted in brain injury, with subsequent development of epilepsy. As well as conditions or syndromes associated with epilepsy independent of associated hypoglycaemia such as Hyperinsulinism/Hyperammonia syndrome.
We selected studies, dealing with the misdiagnosis of hypoglycaemic episodes as epileptic seizures. Either by formal diagnosis or treating the episodes with anti-epileptic medications. Clinical information extracted from the articles if available included initial diagnosis, description of seizure/event as well as duration, cause of hypoglycaemia, EEG findings, imaging findings, time from the first event to correct diagnosis, outcome after correct diagnosis.
4. Results
22 cases were identified, from 19 case reports and one case series, in which hypoglycaemic episodes were misdiagnosed or mistreated as epilepsy.
4.1 Initial diagnosis
The initial diagnosis in 17 of the 22 cases was focal epilepsy, 7 of which specified temporal lobe epilepsy. One patient was diagnosed with Juvenile Myoclonic epilepsy, and the others were non-specific.
4.2 Types of the seizure event
Four cases described bilateral tonic-clonic activity only, while another four described progression to bilateral tonic-clonic activity. Other events varied considerably, movements or behaviours were often described as "bizarre". Sweating and automatisms were described in three different cases each. The most common unifying feature in these cases was a predilection for early morning or nocturnal events. Nine cases reported mainly early morning events, while 4 described mainly nocturnal events.
4.3 Duration of events
The duration of episodes varied from minutes to a few hours. However, events commonly lasted more than 20 mins in duration. The duration of the event was not mentioned in 6 cases.
4.4 The cause of the hypoglycaemia
Insulinoma was by far the most common cause of hypoglycaemia misdiagnosed as epilepsy reported in the literature. It was the diagnosis in 20 of the 22 cases. Other causes of recurrent hypoglycaemia included hypopituitarism and persistent hyperinsulinemic hypoglycaemia of infancy. Exogenous insulin is a far more common cause of hypoglycaemia than insulinoma, however, given the higher index of suspicion for hypoglycaemia in patients with diabetes, it is less likely to be misdiagnosed, and perhaps less likely to be published in the literature. One case not included in our results reported focal epileptic seizure induced by transient hypoglycaemia in insulin-dependant diabetes, however, the hypoglycaemia was identified before anti epileptic treatment was commenced, and focal epilepsy was still considered a likely diagnosis, with the hypoglycaemia just facilitating the seizure. [
Brain imaging did not identify a potentially epileptic lesion in the majority of cases, however, 2 cases had incidental lesions including an arachnoid cyst and meningioma, which likely reassured the treating clinicians that epilepsy was the correct diagnosis. Brain imaging was not reported in 6 cases, with only computed tomography [CT] imaging performed in two cases.
4.6 EEG
Interictal EEG abnormalities mainly showed focal slowing, but spike or sharp wave abnormalities were also seen, 7 cases showed no abnormalities. An ictal EEG was available in 6 cases. All of which described diffuse slowing, with one described as bihemispheric slowing but the increase in delta activity was more prominent posteriorly [
4.7 Time from the first event to correct diagnosis
The time from the first event to correct diagnosis was reported in 20 of the 22 cases and ranged from 2 weeks to 8 years. With a median duration of 10 months.
4.8 Follow up
After the correct diagnosis, anti-epileptic medication was stopped or not specified, with no further events at follow up in all patients.
Follow up period ranged from 3 to 70 months. Five patients had a follow-up EEG, having previously had an abnormal interictal EEG. All five follow up EEGs had returned to normal.
“bizarre” feelings in her entire body, amnesia, occasional speech or reading difficulties, confusion, disorientation, and abnormal behaviour/ 10 - 30 min
Insulinoma-6 months
Interictal: revealed asynchronous, bilateral, temporal spikes and waves. EEG during sleep showed bilateral, independent, delta slow waves.
bilateral tonic clonic + episodes of confusion characterized by unresponsiveness and psychomotor slowing./ 5–30 mins
Insulinoma-6 months
Interictal: normal background activity, bilateral synchronous and asynchronous high-amplitude delta waves over the parietotemporal regions, and right frontal sharp-slow waves
diplopia, a feeling of warmth and sweating, followed by clutching of the knees to the chest, occasional tongue biting, subsequent amnesia of event./ 20 - 40 min
Insulinoma-not specified
Interictal: normal alpha background activity, spike and slow wave activity was evident in the left anterior temporal area.
fatigue, psychomotor slowing, bizarre behaviors, like crying, “I will die” and aimlessly moving extremities, followed by loss of consciousness/not specified
left arm paresthesias, spreading to the face and lower limbs, gait incoordination, mild agitation, emotional lability, incoherent speech, fatigue/ 20 min to 2 h
It is well established that hypoglycaemia can cause neuroglycopenic symptoms that may be mistaken for epileptic seizures. Certain features such as a temporal relationship with oral intake, especially nocturnal or early morning events, sweating, and prolonged duration may help distinguish recurrent hypoglycaemic events from epileptic seizures.
While tight glycaemic control is highly desirable in diabetes to prevent the long term complications of hyperglycaemia including nephropathy, retinopathy, and peripheral neuropathy, there is an increased risk of hypoglycaemic episodes. Glucose is the primary source of energy in cerebral metabolism, and its depletion quickly leads to impairment of brain function, thereby leading to a variety of neurological disturbances which range from autonomic symptoms, such as sweating and palpitations, to confusion, motor restlessness, and eventually can lead to stupor and coma. Clinical presentations of autonomic symptoms and impairment of awareness can resemble focal seizures. Therefore, without the utilisation of in-depth analysis and video-EEG monitoring, recurrent episodes of hypoglycaemia of any aetiology may lead to a misdiagnosis of epilepsy.
The mechanism underlying seizures in hypoglycaemia is not fully understood. It is thought to be caused by energy depletion leading to neurotransmitter imbalance, causing the release of excitatory neurotransmitters, with resultant neurotoxicity [
In experimentally induced hypoglycaemia there is a decreased alpha and increased theta and delta wave activity, spread diffusely over the cortex, but particularly seen in the parieto-occipital and temporal regions [
Automated detection of hypoglycaemia-induced EEG changes recorded by subcutaneous electrodes in subjects with type 1 diabetes–the brain as a biosensor.
]. The EEG changes are reversible upon administration of glucose. These EEG changes are so consistently observed in hypoglycaemia that efforts are currently underway to develop an EEG-based alarm system for the detection of hypoglycaemia in patients that are hypo-unaware. The strongest indicators of hypoglycaemia on EEG are an increase in the log amplitude of the delta, theta, and alpha band and a decrease in the alpha band centroid frequency and the peak frequency of the unified theta–alpha band [
]. At this point, energy depletion causes a release of endogenous glutamate and aspartate, which saturate the excitatory amino acid receptors, leading to calcium fluxes and membrane breakdown [
The regional vulnerability of hypoglycaemia-induced neurotoxicity in organotypic hippocampal culture: protection by early tetrodotoxin or delayed MK-810.
]. Oxidative stress and presynaptic release and post-synaptic translocation of zinc are also thought to play a role in neuronal necrosis in hypoglycaemia [
Seizures occurring in hypoglycaemia are usually of the generalised tonic-clonic type. Less frequently, hypoglycaemia has been associated with focal seizures or focal neurological deficits. Focal motor seizures associated with hypoglycaemia have been described [
]. Additionally, there have been reports of seizures originating in the temporal lobe and leading to autonomic symptoms similar to those described in our study [
]. In vitro studies showed that experimentally-induced hypoglycaemia in hippocampal explants produced spontaneous seizure-type activity originating in the CA1 region, and leading to an irreversible reduction in synaptic transmission [
]. Therefore, it is important to consider hypoglycaemia as a cause of seizures when they present atypically as focal seizures. However, in this case, hypoglycaemia caused a metabolic encephalopathy, which presented unusually with a paroxysmal event semiologically resembling focal impaired awareness seizures. Hence the importance of EEG recordings in clarifying the exact nature of the event.
This case also demonstrates a case of an abnormal EEG at baseline in a person with type 1 diabetes, though other factors in the patient's history may account for this dysfunction. Whether or not people with diabetes, and a history of repeated episodes of hypoglycaemia have permanently abnormal EEGs remains open to debate. A history of repeated severe episodes of hypoglycaemia has been associated with the permanent occurrence of slower frequencies on EEG (Eeg-Oloffson et al., 1977) [
], with increased delta and theta activity and reduced alpha activity in the frontal regions related to poor glucose control, and temporal EEG abnormalities unrelated to glucose control [
]. Therefore, EEG abnormalities captured in patients with diabetes should be assumed acute in onset, and prompt close monitoring of blood glucose.
6. Conclusion
In conclusion, hypoglycaemic episodes can present in a variety of ways, including paroxysmal events caused by a metabolic encephalopathy. Although uncommon, the semiology of these events, as in our case, can be indistinguishable from focal epileptic seizures. Insulinomas are the most frequent cause of hypoglycaemic episodes misdiagnosed as epilepsy in the literature. The diagnosis of epilepsy in patients on hypoglycaemic medications is particularly difficult, and due care should be taken. Our case highlights the difficulty in the diagnosis and management of epilepsy without the utilisation of continuous video-EEG monitoring. Finally, it demonstrates the potential long-term effects of recurrent hypoglycaemia on electroencephalographic activity, and the specific acute EEG changes related to severe hypoglycaemia, which includes decreased alpha, and increased theta and delta wave activity that spreads diffusely over the cortex. We strongly believe that making a diagnosis of epilepsy within the cohort of patients with insulin-dependant diabetes requires extra consideration to avoid the risk of misdiagnosis of epilepsy, and subsequent exposure to the harmful effects of anti-epileptic therapy Fig. 1, Fig. 2, Fig. 3, Fig. 4a, Fig. 5, Fig. 6, 4a.
Fig. 1EEG at seizure onset, showing diffuse theta slowing more prominent in the temporal regions 4–5 Hz. All EEG's shown at LFF 1 Hz, HFF 70 Hz, Notch off.
Fig. 5Resolution of seizure, but EEG still shows diffuse theta slowing more prominent in the temporal regions 4–5 Hz, with bisynchronous spike and slow-wave maximum anterior.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Funding
FutureNeuro Science Foundation Ireland Research Centre
Automated detection of hypoglycaemia-induced EEG changes recorded by subcutaneous electrodes in subjects with type 1 diabetes–the brain as a biosensor.
The regional vulnerability of hypoglycaemia-induced neurotoxicity in organotypic hippocampal culture: protection by early tetrodotoxin or delayed MK-810.
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