The purpose of our ongoing studies is to develop a hypoglycemia alarm based on continuous measurements of EEG and automated real-time analysis. Iaione and Marques14
published the development of an automated algorithm using digital signal processing and artificial neural networks with the aim of developing a hypoglycemia detector system. They achieved a fair performance, but to our knowledge, the concept was not commercialized. Our aim is to develop a portable real-time hypoglycemia alarm device for T1DM patients with hypoglycemia unawareness. For such a device to be suitable for clinical use, it must fulfill a number of criteria: it must have a high sensitivity and an infrequent occurrence of false positive alarms, it must be suitable for long-term use with minimal discomfort for the patient, and, preferably, it should require little or no calibration.
One of our initial insulin-induced hypoglycemia studies demonstrated that the majority of patients develop EEG changes ahead of cognitive deterioration.5
By repeating the experiments in a subgroup of the patients, the presence of an individual glucose threshold for EEG changes was confirmed. In another study, the concept of a real-time alarm device was tested.15
We found that most patients received an alarm in proper time to take action and were able to prevent impending severe hypoglycemia by carbohydrate intake. The study was carried out both during daytime and sleep, underscoring that it was possible to differentiate the characteristic EEG sleep patterns from hypoglycemia-associated EEG changes. If an alarm device shall be used without extensive individual calibration, it is of utmost importance that the hypoglycemia-associated EEG changes are similar in all patients. A large data set is required to address this issue. Therefore, in this article, we have pooled data from different trials conducted so far. This gathering of data from different protocols, none of which is recorded for the actual purpose of this study, constitutes a weakness of the present study.
However, the hypoglycemia induction procedure was similar in all protocols. Additionally, EEG signals recorded with subcutaneous and cup/cap electrodes are comparable regarding amplitude and frequency distribution. We have conducted a number of parallel recordings confirming this during our development. Furthermore, for each patient, the normoglycemic and hypoglycemic EEG sequences were part of one continuous recording, thereby being conducted during the exact same circum-stances. Accordingly, the significant and stable changes in the qEEG variables are unlikely to be caused by differences in study procedures. If anything, it may tend to obliterate differences, underscoring the fact that qEEG changes are not dependent on procedure. We found that hypoglycemia-associated EEG changes are independent of age and duration of diabetes.
Regarding gender, a significant difference in an important hypoglycemia indicator was found since a larger increase of absolute amplitude in the theta band in female subjects compared with male subjects was demonstrated. However, taking into account the small difference as compared with the hypoglycemia versus normoglycemia, this is likely to be caused by multiple testing. In a previous study in T1DM patients conducted during euglycemic condition, it was demonstrated that female gender is associated with higher values of delta power.16
Age, age at diabetes onset, and duration of diabetes has been shown not to influence the baseline EEG in diabetes subjects.16
With respect to hypoglycemia awareness status, we found some qEEG change discrepancies across the subgroup (beta amplitude, alpha and beta centroid frequency). Bendtson and coauthors6
found that only patients with abolished glucagon release expressed hypoglycemia-related EEG changes and suggested that glucagon has a protective action on the brain during hypoglycemia. Although the awareness status of the patients was not given in that study, it may be assumed that the glucagon nonresponders were also the patients with impaired awareness of hypoglycemia. Earlier, we found that EEG changes were independent of glucagon release.5
In a study of nondiabetic patients, insulin-induced hypoglycemia was ceased either by glucose or glucagon injection. In accordance with our observation, no protective effect of glucagon on EEG changes was found.17
From the data in the present study, it is not possible to explain the EEG response difference between patients with unawareness and patients with sustained awareness. Because this difference seems independent of age, duration of diabetes, and glucagon response, unawareness and altered hypo-glycemia-associated EEG changes may share a rather common course. The hypoglycemia alarm device will be directed primarily toward patients suffering from unawareness. However, since awareness status is likely to be a dynamic rather than permanent condition, it will be necessary to look closely at potentially dynamic differences in hypoglycemia-associated EEG changes. Such is the focus of ongoing studies.
It remains controversial whether patients with diabetes have EEG aberrations as compared with nondiabetic individuals during euglycemia conditions. Previous reports have demonstrated a significant loss of fast oscillations (alpha and beta activity) in the posterior temporal regions of diabetes patients.16
In another published study, however, EEG was recorded during childhood diabetes and was repeated in adulthood 16 years later.18
The data were stratified according to the prevalence of severe hypoglycemia during childhood. This prospective study, which can be assumed to be sensitive with regard to long-term consequences of severe hypoglycemia, failed to confirm the prevalence of persistent EEG changes. Therefore, the detected EEG changes must be ascribed to the acute hypoglycemia.