Lars Hyllienmark

Subclinical nerve dysfunction in children and adolescents with IDDM

SummaryThe purpose of this study was to investigate whether young insulin-dependent diabetic patients still develop peripheral nerve dysfunction when using modern multiple insulin injection therapy and to elucidate if this correlated with various disease parameters. Seventy-five patients, 7 to 20 years old with a duration of diabetes of more than 3 years, and 128 age-matched healthy control subjects underwent bilateral studies of median, peroneal, and sural nerves. Presence of diabetes lowered motor conduction velocity (p<0.0001), sensory conduction velocity (p<0.0001) and sensory nerve action potential (p<0.05) in all examined nerves. The mean change in conduction velocity induced by diabetes was −4.8 m/s in the peroneal nerve, −3.3 m/s in the median motor nerve, −2.6 m/s in the sural nerve and −2.4 m/s in the median sensory nerve. Fifty-seven percent of the patients had abnormal conduction (values outside 95% predictive interval) which was seen most often in the motor nerves, especially in the peroneal nerve (41%) followed by the median nerve (24%). In multiple regression analysis, long-term poor metabolic control and increased body length correlated with nerve dysfunction identified in most examined parameters. Three patients had signs or symptoms suggestive of neuropathy. It is concluded that despite modern multiple insulin injection therapy, with reasonably good metabolic control, nerve dysfunction is still common in children and adolescents with insulin-dependent diabetes mellitus. Risk factors are increased height and long-term poor metabolic control.

EEG abnormalities with and without relation to severe hypoglycaemia in adolescents with type 1 diabetes

Aims/hypothesisThe aim of the present study was to identify whether adolescents with type 1 diabetes receiving modern multiple insulin injection therapy (MIT) have abnormal EEGs, and to elucidate possible correlations with a history of severe hypoglycaemia, poor metabolic control and nerve conduction defects.MethodsWe investigated 35 patients (age 14–19 years) with disease duration 7.6±4.6 years, and 45 healthy control subjects. EEG spectral components were obtained from 15-min recordings in resting, awake subjects. Nerve conduction was measured bilaterally in motor and sensory fibres in the median, peroneal and sural nerves.ResultsThe EEGs of patients showed an increase in slow activity (delta and theta) and a reduction in alpha peak frequency, both of which were most pronounced in the frontal regions (p<0.001). They also showed a decrease in fast activity, which was most pronounced bilaterally in the posterior temporal regions (alpha p<0.001, beta p<0.01, gamma p<0.001). A history of severe hypoglycaemia was correlated with a global increase in theta activity (p<0.01–0.05). Poor metabolic control, measured as acute and long-term HbA1c levels, was correlated with an increase in delta activity and a decrease in alpha peak frequency. The decrease in fast activity in the temporal regions was a separate type of abnormality because it had a different distribution, and was not correlated with the increase in delta/theta power, poor metabolic control or with hypoglycaemia.Conclusions/interpretationRecurrent severe hypoglycaemia and poor metabolic control are risk factors for EEG abnormalities in adolescents with type 1 diabetes receiving MIT treatment. In addition, we found pronounced abnormalities in the temporal regions that were not related to these risk factors.

Early diabetic complications in a population of young patients with type 1 diabetes mellitus despite intensive treatment.

AIM To describe the prevalence of early complications in an unselected population of patients with type 1 diabetes mellitus (DM1) diagnosed in childhood with intensive insulin treatment from diagnosis. METHODS Eighty children and adolescents with DM1, age 7-22 years and DM1 duration >3 years, were studied. Neuropathy was defined as abnormal nerve conduction finding in > or = 2 of 4 nerves (sural and peroneal nerves), nephropathy as albumin excretion rate > or = 20 microg/min and retinopathy as all grades of retinal changes in fundus photographs. RESULTS The prevalence of neuropathy was 59%, of retinopathy 27% and of nephropathy 5% after 13 years DM1 duration. Mean (SD) long-term HbA1c was 8.4 (0.9)% (DCCT-corrected value). CONCLUSION Even in a population with intensive insulin treatment from the beginning and fairly good metabolic control, the prevalence of subclinical neuropathy was high, while other diabetic complications were lower than usually reported.

Impaired microvascular function related to poor metabolic control in young patients with diabetes

The purpose of the present study was to identify whether young patients with type 1 diabetes using modern multiple insulin injection therapy (MIT) have signs of microvascular dysfunction and to elucidate possible correlations with various disease parameters. Skin blood flow on the dorsum of the foot was measured with laser Doppler perfusion imaging in 37 patients (age 10–21 years, disease duration 6·0–16 years) and 10 healthy controls. Measurements were performed at rest, after change in posture (the leg was lowered below heart level) and during postocclusive hyperaemia. Following a change in posture blood flow increased instead of decreased in a majority of the study subjects. Patients with acute HbA1c >7·5% (n = 22) had an increase in skin blood flow at rest and a significantly reduced blood flow when the leg was lowered below heart level as compared with patients with HbA1c <7·5% (0·26 V versus 0·17 V, P<0·01 and 0·12 V versus 0·23 V, P<0·05, respectively) and healthy controls. Following occlusion of the macrocirculation for 3 min a small non‐significant decrease in the hyperaemic response was seen in the patients. The postocclusive hyperaemic response and the venoarteriolar reflex were not correlated to duration of disease, long‐term metabolic control or electrophysiological signs of peripheral nerve dysfunction. It is concluded that signs of microvascular dysfunction related to poor metabolic control are present in young patients with MIT treatment and rather well‐controlled diabetes. Low resting blood flow levels are suggested to contribute to the absence of postural vasoconstrictor response.

Decreased cortical connectivity and information flow in type 1 diabetes

OBJECTIVE To investigate the effect of type 1 diabetes on EEG connectivity and information flow and study the relationship between these parameters and electrophysiological, neuropsychological and clinical variables. METHODS Connectivity was assessed using several measures (phase coherence, phase lag index, synchronization likelihood and phase slope index) on 119 patients and 61 healthy controls over several frequency bands (between 0.5 and 45 Hz). Data was further correlated to EEG power, event related potentials, neuropsychological function and demographic variables. RESULTS Multivariate test on the connectivity data showed a difference between patients and controls both with mastoid reference (p<0.01) and current source density estimates (p<0.04). Connectivity and information flow correlated with EEG power but not with event related potentials or neuropsychological function. CONCLUSIONS Connectivity and information flow are decreased in diabetes. These variables assess other functions of the brain than captured by the present cognitive tests. Several tests need to be performed in order to monitor the effect of diabetes on brain function. SIGNIFICANCE The decrease in connectivity and cortical information flow are EEG abnormalities that add to the previously described EEG and ERP abnormalities described for type 1 diabetes.

Normal values of nerve conduction in children and adolescents

Healthy children and adolescents (n = 128) ranging in age from 6 to 20 years and in height from 114 to 193 cm underwent studies of median, peroneal and sural nerves bilaterally, including nerve conduction velocity, amplitude and motor distal latencies. Arms and legs were heated in all subjects to obtain skin temperatures around 34 degrees C. Both motor and sensory nerve conduction velocities were found to correlate more with height than with age. There was a strong negative correlation between height and peroneal conduction velocity (r = -0.40, P < 0.0001). On the contrary, a positive correlation was found between height and both median sensory (r = 0.30, P < 0.0001) and motor (r = 0.22, P < 0.001) conduction velocities. Skin temperature, even near 34 degrees C, had a strong effect on conduction velocity and motor distal latencies. It is concluded that consideration of height and temperature will improve the diagnostic safety of nerve conduction measurements in children and young adults.

A mechanistic model of mismatch negativity in the ageing brain.

OBJECTIVE We investigated the neurophysiological mechanisms underpinning the generation of the mismatch negativity (MMN) in the ageing brain. METHODS We used dynamic causal modelling (DCM) to study connectivity models for healthy young and old subjects. MMN was elicited with an auditory odd-ball paradigm in two groups of healthy subjects with mean age 74 (n=30) and 26 (n=26). DCM was implemented using up to five cortical nodes. We tested models with different hierarchical complexities. RESULTS We showed that the network generating MMN consisted of 5 nodes that could modulate all intra- and inter-nodal connections. The inversion of this model showed that old subjects had increased input from rSTG to the rIFG (p<0.01) together with increased inhibition of pyramidal cells (p<0.05). Furthermore, there was reduced modulation of activity within rIFG (p<0.02) on stimulus change. CONCLUSION The age related change in MMN is due to a decline in frontal-based control mechanisms, with alterations in connectivity between temporal and frontal regions together with a dysregulation of the excitatory-inhibitory balance in the rIFG. SIGNIFICANCE This study provides for the first time a neurobiological explanation for the age related changes of the MMN in the ageing brain.

Nerve conduction defects are retarded by tight metabolic control in type I diabetes.

This follow‐up study examines whether the development of nerve dysfunction is retarded by tight metabolic control in patients with type I diabetes mellitus. Seventy‐one patients and 115 age‐matched healthy control subjects underwent studies of nerve conduction in peroneal and sural nerves. The presence of diabetes was associated with a reduction in peroneal motor nerve conduction velocity (MCV) by 5.9 m/s, sural sensory nerve conduction velocity (SCV) by 3.4 m/s, and sural sensory nerve action potential (SNAP) amplitude by 22%. Dysfunction in peroneal MCV, sural SCV, and sural SNAP were related to long‐term poor metabolic control. Eleven of 12 patients with HbA1c <6.5% had normal nerve conduction or abnormality in only one nerve as compared to 2 of 15 patients with HbA1c >8.0%. It is concluded that tight long‐term metabolic control (HbA1c <6.5%) can retard nerve dysfunction in patients with type I diabetes mellitus and a mean disease duration of 12 years.

The maturation of mismatch negativity networks in normal adolescence

OBJECTIVE We investigated the neurophysiological mechanisms underpinning the generation of the mismatch negativity (MMN) and its development from adolescence to early adulthood. METHODS We used dynamic causal modelling (DCM) to study connectivity models for healthy adults and adolescents. MMN was elicited with an auditory oddball paradigm in two groups of healthy subjects with mean age 14 (n=52) and 26 (n=26). We tested models with different hierarchical complexities including up to five cortical nodes. RESULTS We showed that the network generating MMN consisted of 5 nodes that could modulate all intra- and internodal connections. The inversion of this model showed that adolescents had reduced backward connection from rIFG to rSTG (p<0.04) together with increased excitatory activity in rSTG (p<0.02). There was a reduced modulation of excitability in rSTG (p<0.02) and of forward connectivity from lA1 to lSTG (p<0.03). CONCLUSION The cortical network generating MMN continues to develop in adolescence up to adulthood. Cortical regions in the temporal and frontal lobes, involved in auditory processing, mature with increasing fronto-temporal connectivity together with increased sensitivity in the temporal regions for changes in sound stimuli. SIGNIFICANCE This study may offer an explanation for the neurobiological maturation of the MMN in adolescence.

Abnormal cold perception in the lower limbs : a sensitive indicator for detection of polyneuropathy in patients with type 1 diabetes mellitus

Diabetic peripheral neuropathy differs in type 1 and type 2 diabetes. The aim of this study was to evaluate how signs and symptoms of neuropathy correlated with defects in motor and sensory nerve conduction velocity (MCV and SCV) and sensory perception thresholds in patients with type 1 diabetes. MCV and SCV in peroneal and sural nerves and vibratory, warm and cold perception thresholds (VPT, WPT, CPT) were evaluated in the lower limbs of 127 patients (42+/-7.9 years old, duration of diabetes, 16+/-11 years and HbA1c, 7.7+/-1.4%). The results were compared with clinical findings (neuropathy impairment assessment, NIA) and sensory symptoms (neurological symptom assessment, NSA). Sensory symptoms were present in 24% of patients, 91% had at least one abnormal finding in the neurological examination and 84% had abnormal nerve conduction. The greatest deviation from normal was observed for CPT on the dorsum of the foot and peroneal MCV. NIA and NSA correlated with all electrophysiological measurements in the foot and big toe. It is concluded that clinical findings correlate well with electrophysiological abnormalities in patients with type 1 diabetic neuropathy. An elevated CPT for the foot was the most pronounced sensory defect.