Effect of Hypoglycaemia on Cerebral Blood Flow and Structure

Hypoglycaemia promotes a redistribution of regional cerebral blood flow (Tallroth et al., 1992; MacLeod et al., 1994; Kennan et al., 2005) which may encourage localised neuronal ischaemia, particularly if the cerebral macro- or microcirculation is already compromised in subjects with type 1 diabetes. Using techniques such as Single Photon Emission Tomography, the blood flow to the frontal lobes has been shown to be increased during acute hypoglycaemia in non-diabetic subjects (Tallroth et al., 1992). In patients with a history of previous severe hypoglycaemia (MacLeod et al., 1994), and in patients with impaired hypoglycaemia awareness (MacLeod et al., 1996), this altered pattern in

Frontal

Encourage Blood Flow Brain

Figure 13.4 Schematic representation of regions of interest in the brain in a neuroanatomical template used for transaxial (horizontal) slices at the level of the basal ganglia, examining cerebral blood flow. By using single photon emission tomography (SPET) during acute hypoglycaemia, increased uptake of isotope in the frontal area indicated increased blood flow while in the calcarine area it was reduced compared to euglycaemia, thus demonstrating redistribution of regional blood flow (MacLeod etal., 1994)

Figure 13.4 Schematic representation of regions of interest in the brain in a neuroanatomical template used for transaxial (horizontal) slices at the level of the basal ganglia, examining cerebral blood flow. By using single photon emission tomography (SPET) during acute hypoglycaemia, increased uptake of isotope in the frontal area indicated increased blood flow while in the calcarine area it was reduced compared to euglycaemia, thus demonstrating redistribution of regional blood flow (MacLeod etal., 1994)

regional cerebral blood flow appears to be a permanent sequel (Figure 13.4). This permanent increase in regional cerebral blood flow to the frontal lobes may be an adaptive response to protect an area of the brain that is most vulnerable to the effects of hypoglycaemia. This susceptibility of the frontal areas has been shown by other techniques, including EEG (Pramming et al., 1988), and tests of cognitive function (see Chapter 2). Neuropathological observations have indicated that the brain is susceptible to neurogly-copenia in a rostro-caudal direction with the cerebral cortex and hippocampus being most sensitive and the brainstem and spinal cord being most resistant (Auer et al., 1984) (Figure 13.5).

Other imaging techniques of the brain have yielded complementary information about abnormal brain structure in diabetes (Figure 13.6). Studies using CT and MRI scanning have shown a high prevalence of cerebral atrophy in people with diabetes (36-53% compared to 12% in age-matched non-diabetic controls), which occurs earlier in life than in non-diabetic control subjects and tends to be more extensive (Figure 13.7) (Araki et al., 1994). Ventricular enlargement also occurs more frequently in patients with diabetes than in healthy controls (Lunetta et al., 1994).

Studies of the brains of people with diabetes using magnetic resonance imaging (MRI) demonstrated a high prevalence (69% in type 1 diabetes versus 12% in healthy non-diabetic subjects) of small periventricular high-intensity lesions known as 'leukoaraiosis' (Dejgaard et al., 1991). Leukoaraiosis is an age-related radiological finding that is also associated with hypertension, vascular disease, dementia and demyelination (Pantoni and Garcia, 1996). In a recent study using MRI, small subcortical white matter lesions were present in about a third of diabetic patients (Ferguson et al., 2003).

Ceri Hipp

Ceri Hipp

Diagram Hypoglycaemia

Brain stem Spinal cord

Figure 13.5 Diagram indicating the sensitivity of regions of the brain to acute neuroglycopenia. The cortex and hippocampus are most vulnerable and the brainstem and spinal cord are most resistant

Brain stem Spinal cord

Figure 13.5 Diagram indicating the sensitivity of regions of the brain to acute neuroglycopenia. The cortex and hippocampus are most vulnerable and the brainstem and spinal cord are most resistant

Pathologically, leukoaraiosis has non-specific features consisting of areas of gliosis, loss of myelin sheaths and increased water content (Awad et al., 1986). The significance of leukoaraiosis in diabetes is unknown, but may represent localised ischaemia (Brands et al., 2004). In one study it was associated with advanced microvascular diabetic complications (Dejgaard et al., 1991) (Box 13.3). Recently, a high incidence of cerebral atrophy (33%), cerebellar atrophy (11%) and leukoaraiosis (56%) was observed in diabetic patients with the 3243 mitochondrial tRNA mutation (Suzuki et al., 1996). Some abnormal patterns of the appearance of MRI scans of the brain are shown schematically in Figure 13.8.

Structural Changes Associated with Hypoglycaemia (Box 13.4)

Human subjects who have succumbed to severe hypoglycaemia have been studied at postmortem, and are shown to have areas of cortical necrosis, particularly in the frontal lobes and hippocampus, with relative sparing of the hindbrain (Auer et al., 1984). Cortical and hippocampal atrophy and ventricular enlargement have been described in long-term survivors of severe hypoglycaemia (McCall, 1992). The neurohistological features, however, are non-specific and are similar to those of anoxic brain damage. Human studies are further confounded by the fact that many subjects have suffered secondary brain damage as a result of cardiorespiratory collapse (Patrick and Campbell, 1990). In hypoglycaemic brain damage there is selective neuronal acidophilia with shrinkage of the cells which have a bright red

Insulin Overdose Cerebral Damage Mri
Figure 13.6 Common asymptomatic neurological abnormalities observed with MRI in patients with type 1 diabetes: (a) cortical atrophy; (b) ventricular dilatation; (c) leukoaraiosis

cytoplasm (Figure 13.9). These cannot be differentiated from ischaemic neurones, but the pattern of neuronal injury characterises hypoglycaemic damage with cells in specific layers of the cortex being destroyed.

A few case reports have described abnormalities of brain structure detected by CT scanning or MRI, associated with focal neurological deficit following one or more episodes of severe hypoglycaemia. Marked global cerebral atrophy has been described in a young patient with type 1 diabetes within a few months of a severe episode of hypoglycaemia that

Box 13.3 Structural abnormalities of the brain associated with diabetes

Gross pathology

Histological abnormalities*

Severe cerebral atheroma

Meningeal fibrosis

Cerebral infarction

Pseudocalcinosis

Lacunar strokes

Diffuse degeneration of grey

and white matter

Increased endothelial

basement membrane

thickness

Microaneurysms

Abnormal imaging (Figure 13.6)

Cortical atrophy

Ventricular dilatation

Leukoaraiosis

* Some changes were observed in patients who died with coexisting uraemia and hypertension - changes

may not be specific to diabetes.

Brain Hypoglycaemia
Figure 13.7 The prevalence of brain atrophy with increasing age as demonstrated by MRI. This is more common in diabetic subjects (type 1 and type 2) at an earlier age. Reproduced from Araki et al. (1994), with permission from Springer Science and Business Media

Box 13.4 Structural abnormalities of the brain associated with profound hypoglycaemia

Lethal hypoglycaemia Cortical necrosis Hippocampal necrosis

Survivors of severe hypoglycaemia with gross neurological deficit Cortical atrophy Hippocampal atrophy Ventricular dilatation

Patients with severe recurrent hypoglycaemia and no neurological signs Cortical atrophy

Diabetic Mri
Figure 13.8 Diagrammatical representations of the patterns of abnormal appearance observed in MRI scans of brains in subjects with type 1 diabetes
Cerebral Cortex Shrinkage

Figure 13.9 Histopathological appearance of neurones in layer 2 of the parietal cortex destroyed by exposure to severe hypoglycaemia in a fatal case of a patient with type 1 diabetes, showing pronounced shrinkage of neurones which appeared acidophilic and were stained bright red (not demonstrable in black and white print). Photograph by courtesy of Dr G.A. Lammie

Figure 13.9 Histopathological appearance of neurones in layer 2 of the parietal cortex destroyed by exposure to severe hypoglycaemia in a fatal case of a patient with type 1 diabetes, showing pronounced shrinkage of neurones which appeared acidophilic and were stained bright red (not demonstrable in black and white print). Photograph by courtesy of Dr G.A. Lammie was associated with severe neurological deficit and cortical blindness (Gold and Marshall, 1996). Following severe hypoglycaemia, lesions have been located in the hippocampus in diabetic patients with severe amnesia (Chalmers et al., 1991; Boeve et al., 1995). A lesion with similar appearance on MRI (Figure 13.10) was found in the pons of a patient with persistent ataxia and hemiparesis after an episode of severe hypoglycaemia (Perros et al., 1994). Using fluid-attenuated inversion recovery (FLAIR) sequences on MRI or diffusion weighted images (DWI), more and earlier structural abnormalities can be seen in patients who have suffered severe hypoglycaemia (Finelli, 2001). Some of these changes disappeared after 14 days, coinciding with an improvement in the patient's condition (Maekawa et al., 2005).

The neuropathology of mild cognitive impairment (in the absence of abnormal neurological signs) associated with recurrent severe hypoglycaemia is unknown, but may be either a milder form of structural neuronal damage, similar to that described in lethal cases, or a functional (metabolic) defect. In support of the former hypothesis is a study using brain MRI, in which a group of 11 diabetic patients with a history of severe recurrent hypoglycaemia had a high prevalence of cortical atrophy (45%) compared to none in a matched diabetic control group (Perros et al., 1997). A subsequent larger study (Ferguson et al., 2003) found a strong association between leukoaraiosis and retinopathy, but not with hypoglycaemia, suggesting that leukoaraiosis represents a microvascular complication of hyperglycaemia. A meta-analysis of several studies on the relationship between type 1 diabetes and cognitive impairment confirmed that such an association exists and is associated with microvascular complications (Brands et al., 2005). Therefore, it appears that subtle structural changes (leukoaraiosis) frequently seen on brain imaging of diabetic subjects are more likely to be related to microvascular complications of poor control rather than hypoglycaemia. This

High Signal Intensity Pons

Figure 13.10 MRI scan showing an irregular area of high signal intensity in the left pons in a patient with type 1 diabetes who suffered permanent ataxia and hemiparesis following a single episode of severe hypoglycaemia. Reproduced from Perros et al. (1994) with permission from The American Diabetes Association

Figure 13.10 MRI scan showing an irregular area of high signal intensity in the left pons in a patient with type 1 diabetes who suffered permanent ataxia and hemiparesis following a single episode of severe hypoglycaemia. Reproduced from Perros et al. (1994) with permission from The American Diabetes Association premise is supported by the results of a recent functional MRI study of people with type 1 diabetes with proliferative diabetic retinopathy (Wessels et al., 2006).

Mechanisms of Hypoglycaemia-induced Brain Injury

The principal mechanism by which hypoglycaemia leads to its acute neuropsychological manifestations is thought to be the direct effect of lack of glucose on neurones, causing energy failure. Cerebral glycogen stores (albeit limited) may be important in curtailing the effects of hypoglycaemia, though the importance of this glucose source in human subjects is unknown (Gruetter et al., 2003; McCall, 2004). Additional alterations in the cerebral circulation induced by hypoglycaemia may cause transient and localised ischaemia, provoking focal neurological abnormalities such as hemiparesis. Less is known about the pathogenesis of permanent neurological damage following severe prolonged hypoglycaemia. In animal models, activation of postsynaptic neurocytotoxin receptors by neurotransmitters (glutamate and N-acetyl aspartate) released from presynaptic neurones as a result of hypoglycaemia, appear to be an important cause of neuronal death (Cotman and Iversen, 1987; Choi, 1990; Auer, 2004). Increased influx of calcium, which may be linked to stimulation of neurocytotoxin receptors, is also toxic and can cause cell death (Siesjo and Bengsston, 1989). These mechanisms may explain the selective nature of hypoglycaemia-induced neuronal damage which spares glial and vascular tissue in the brain.

Evidence for Diabetic Encephalopathy

Considerable evidence indicates an association between neuropsychological dysfunction and diabetes. The nature of this association is unclear but four main contributing factors have been identified:

• poor glycaemic control;

• cerebrovascular disease;

• hypoglycaemia;

• the psychosocial impact of diabetes per se.

Hypoglycaemia is of particular importance because it is potentially avoidable, and the subtle cumulative effects on cognitive function may not be noticed until its severity compromises the social and psychological functioning of the affected individual. The misplaced enthusiasm with which some health professionals (and patients) pursue and implement strict glycaemic control when this may not be prudent or appropriate (such as in people with impaired awareness of hypoglycaemia), may place some people at risk of developing diabetic encephalopathy. In a clinical context, severe hypoglycaemia is encountered in three broad categories of patients:

• patients with type 1 diabetes who have strict glycaemic control with no or minimal microvascular complications;

• patients with long duration of type 1 diabetes, moderate or poor glycaemic control (often due to inadequate diabetes self-management, erratic lifestyle, inappropriate insulin dose or regimen, coexistent social and psychological problems), associated with advanced microvascular complications;

• patients who have suffered a single devastating episode of hypoglycaemia as a result of deliberate or accidental overdose of insulin or sulphonylurea.

Whereas the evidence so far suggests that younger patients in the first category (resembling the highly selected population of patients with type 1 diabetes studied in the DCCT) may not be susceptible to cumulative cognitive deterioration (Reichard and Pihl, 1994; The Diabetes Control and Complications Trial Research Group, 1996; 1997), in clinical practice a sizeable proportion of patients belongs to the second category. They have elevated glycated haemoglobin concentrations and established microvascular complications. It has been suggested that hypoglycaemia can aggravate established micro- and macrovascular disease (Fisher and Frier, 1993) and potentiate the risk of hypoglycaemia-induced damage to the brain. The evidence from retrospective studies suggests that chronic deterioration in cognitive function may be a real risk should the conclusions of the DCCT be applied indiscriminately to these patients (Deary and Frier, 1996).

The effects of diabetes on the brain have been reviewed by Ryan (2006), who suggests that there is little evidence to support a classical 'diabetic encephalopathy'. Although cognitive dysfunction does exist, in most people with type 1 diabetes the changes are subtle and represented principally as mental slowing, similar to that observed with ageing. This may be a manifestation of chronic hyperglycaemia, and not recurrent exposure to severe hypoglycaemia.

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