RATIONAL THERAPY AND REMISSION IN DIABETES MELLITUSThe evidence for MRI detection of hypoglycemic brain injury

ByRoberto Victor Illa, M.D.

© 2004 ALL RIGHTS RESERVED

Are there documented adverse macrovascular complications to the ADA/DCCT Tight Control Protocol? What is the Emperor wearing?

Oligodendroglia

Cells of the CNS include neurons, glia, and microglia. Neurons have many ribosomes, since they synthesize proteins and other substances very actively. Generally, neurons do not divide, although recent research indicates that there may be some limited capacity for division in post-natal life. The neurons are composed of a cell body, dendrites, which receive signals, and an axon. The axon may be very long and culminates in synaptic processes that release neurotransmitters. The axon is surrounded by a sheath of myelin, which insulates the axon and makes transmission of nerve impulses much more efficient. The axon also contains neurofilaments and microtubules, both of which serve an essential role in transport of substances through the neuron. Glia include astrocytes and oligodendroglia. Astrocytes are so named because they look like stars. They may react to disease processes by forming scar tissue. They have a metabolic relationship with neurons, and they contribute to the “blood-brain barrier,” which makes it more difficult for blood-borne substances to enter the brain than other bodily tissues.

The oligodendroglia form myelin in the white matter. In the gray matter,

they are “satellite cells” that “hug” the neurons. The gray matter of the CNSconsists of cells bodies; the white matter contains many axons, which arewhite due to the insulating myelin. Microglia are macrophages that reside inthe nervous system. They are usually not very apparent in a healthy brain.

Oligodendroglia are more susceptible to oxidative stress

Neurosci Biobehav Rev. 1997 Mar;21(2):151-66. Related Articles, Links Response of glial cells to ischemia: roles of reactive oxygen species and glutathione. Juurlink BH. Saskatchewan Stroke Research Centre, Saskatoon, Canada.

A review of reactive oxygen species (ROS) is followed by a discussion on the differential susceptibility of astrocytes and oligodendroglia to ischemia-related insults. Astrocytes can survive chronic hypoxia as well as long periods of simulated ischemia, i.e. hypoglycemia and anoxia.

Oligodendroglia are preferentially injured over astrocytes by chronic hypoxia, reperfusion following ischemia, hypoglycemia or uncoupling of oxidative phosphorylation. Increasing the generation of ROS in mixed glial cultures by adding ROS generators results in preferential death of oligodendroglia.

Oligodendroglia are more susceptible to oxidative stress because they have low glutathione contents while concomitantly having higher iron contents and are more dependent upon oxidative phosphorylation than are astrocytes. Glutathione plays a pivotal role in the ROS-scavenging strategies of the cell while iron plays a pivotal role in the generation of hydroxyl, peroxy and akoxy radicals. These in vitro findings delineate the physiological basis for the white matter damage seen in adults following prolonged periods of hypoperfusion and the damage seen in the oligodendroglial germinal zones resulting in periventricular leukomalacia seen following in utero hypoxia-ischemia.

Periventricular white matter injury in rats made hypoglycemic with insulin

Acta Neuropathol (Berl). 1984;64(3):177-91. The distribution of hypoglycemic brain damage. Auer RN, Wieloch T, Olsson Y, Siesjo BK.

Rats were exposed to insulin-induced hypoglycemia resulting in periods of cerebral isoelectricity ranging from 10 to 60 min. After recovery with glucose, they were allowed to wake up and survive for 1 week. Control rats were recovered at the stage of EEG slowing. After sub-serial sectioning, the number and distribution of dying neurons was assessed in each brain region. Acid fuchsin was found to stain moribund neurons a brilliant red. Brains from control rats showed no dying neurons. From 10 to 60 min of cerebral isoelectricity, the number of dying neurons per brain correlated positively with the number of minutes of cerebral isoelectricity up to the maximum examined period of 60 min.

Neuronal necrosis was found in the major brain regions vulnerable to several different insults. However, within each region the damage was not distributed as observed in ischemia. A superficial to deep gradient in the density of neuronal necrosis was seen in the cerebral cortex. More severe damage revealed a gradient in relation to the subjacent white matter as well. The caudatoputamen was involved more heavily near the white matter, and in more severely affected animals near the angle of the lateral ventricle. The hippocampus showed dense neuronal necrosis at the crest of the dentate gyrus and a gradient of increasing selective neuronal necrosis medially in CA1. The CA3 zone, while relatively resistant, showed neuronal necrosis in relation to the lateral ventricle in animals with hydrocephalus. Sharp demarcations between normal and damaged neuropil were found in the hippocampus. The periventricular amygdaloid nuclei showed damage closest to the lateral ventricles. The cerebellum was affected first near the foramina of Luschka, with damage occurring over the hemispheres in more severely affected animals. Purkinje cells were affected first, but basket cells were damaged as well. Rare necrotic neurons were seen in brain stem nuclei. The spinal cord showed necrosis of neurons in all areas of the gray matter. Infarction was not seen in this study. The possibility is discussed that a neurotoxic substance borne in the tissue fluid and cerebrospinal fluid (CSF) contributes to the pathogenesis of neuronal necrosis in hypoglycemic brain damage.

Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes.

Manschot SM, Brands AM, van der Grond J, Kessels RP, Algra A, Kappelle LJ, Biessels GJ; Utrecht Diabetic Encephalopathy Study Group. Diabetes. 2006 Apr;55(4):1106-13.

Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. s.m.manschot@umcutrecht.nl

The structural correlates of impaired cognition in type 2 diabetes are unclear. The present study compared cognition and brain magnetic resonance imaging (MRI) between type 2 diabetic patients and nondiabetic control subjects and assessed the relationship between cognition and MRI findings and blood pressure and metabolic control. The study included 113 patients and 51 control subjects.

Brain MRI scans were rated for white matter lesions (WMLs), cortical and subcortical atrophy, and infarcts. Neuropsychological test scores were divided into five cognitive domains and expressed as standardized Z values.

Type 2 diabetes was associated with deep WMLs (P = 0.02), cortical (P < 0.001) and subcortical (P < 0.05) atrophy, (silent) infarcts (P = 0.06), and impaired cognitive performance (attention and executive function, information-processing speed, and memory, all P < 0.05). Adjustment for hypertension did not affect the results.

Within the type 2 diabetic group, cognitive function was inversely related with WMLs, atrophy, and the presence of infarcts (adjusted for age, sex, and estimated IQ), and there was a modest association with HbA1c and diabetes duration. This association was strongest for age, even more so than in control subjects. We conclude that cognitive impairments in patients with type 2 diabetes are not only associated with subcortical ischemic changes in the brain, but also with increased brain atrophy.

The cognitive correlates of white matter abnormalities in normal aging

Neuropsychology. 2000 Apr;14(2):224-32.

The cognitive correlates of white matter abnormalities in normal aging: a quantitative review.

Gunning-Dixon FM, Raz N.

Department of Psychology, University of Memphis, Tennessee 38152-6400, USA.

Cerebral white matter of asymptomatic people frequently exhibits circumscribed areas of hyperintensity on magnetic resonance (MR) images and hypodensity on computed tomography scans. However, behavioral implications of this phenomenon remain unclear. In this meta-analysis, the authors examine cumulative evidence regarding the cognitive sequelae of white matter abnormalities in adults without dementia. The influence of potential moderator variables, such as neuroimaging technique, location of the lesions, rating scale, and demographic characteristics of the sample on the association between the burden of white matter hyperintensities and cognitive performance was also examined. Results indicate that white matter abnormalities observed on MR images are associated with attenuated performance on tasks of processing speed, immediate and delayed memory, executive functions, and indices of global cognitive functioning. There was no significant link between the white matter hyperintensities and psychometric indices of intelligence or fine motor performance.

Specific changes in human brain after hypoglycemic injury.

Stroke. 1997 Mar;28(3):584-7.

Specific changes in human brain after hypoglycemic injury.

Fujioka M, Okuchi K, Hiramatsu KI, Sakaki T, Sakaguchi S, Ishii Y.

Department of Neurosurgery, Nara Medical University, Japan. RXL00203@niftyserve.or.jp

BACKGROUND AND PURPOSE: Very few reports are available on serial changes in the human brain after severe hypoglycemic injury. The aim of this study was to investigate sequential neuroradiological changes in brains of patients after hypoglycemic coma compared with those after cardiac arrest previously studied with the same methods. METHODS: We repeatedly studied CT scans and MR images obtained at 1.5 T in four vegetative patients after profound hypoglycemia associated with diabetes mellitus. RESULTS: In all patients, consecutive CT scans showed symmetrical, persistent low-density lesions with transient enhancement in the caudate and lenticular nuclei and transient enhancement in the cerebral cortex 7 to 14 days after onset. Serial MR images consistently revealed symmetrical lesions of persistent hyperintensity and hypointensity on T1- and T2-weighted images, respectively, in the caudate and lenticular nuclei, cerebral cortex, substantia nigra, and/or hippocampus from 8 days to 12 months after onset. CONCLUSIONS: Repeated MR images revealed specific lesions in the bilateral basal ganglia, cerebral cortex, substantia nigra, and hippocampus, which suggests the particular vulnerability of these areas to hypoglycemia in the human brain. We speculate that the localized lesions represent tissue degeneration, including some combination of selective neuronal death, proliferation of astrocytic glial cells, paramagnetic substance deposition, and/or lipid accumulation. The absence of localized hemorrhages on MR images in hypoglycemic encephalopathy is in marked contrast to the presence of regional minor hemorrhages in postischemic-anoxic encephalopathy.

Brain abnormalities demonstrated by magnetic resonance imaging in adult IDDM patients with and without a history of recurrent severe hypoglycemia.

Diabetes Care. 1997 Jun;20(6):1013-8. Perros P, Deary IJ, Sellar RJ, Best JJ, Frier BM.

Department of Diabetes, Royal Infirmary of Edinburgh, U.K.OBJECTIVE: Previous studies of a cohort of 100 patients with IDDM have shown that a history of recurrent severe hypoglycemia is associated with a modest impairment of cognitive function. The aim of the present study was to determine whether IDDM patients with and without a history of severe hypoglycemia have lesions in the brain that are identifiable by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) and to investigate the putative relationship of any structural brain abnormalities with cognitive function. RESEARCH DESIGN AND METHODS: MRI and MRS of the brain were performed in 22 patients from the original cohort. Eleven IDDM patients with no history of severe hypoglycemia (group A) were compared with 11 IDDM patients who had a history of five or more episodes of severe hypoglycemia (group B). RESULTS: Nine patients (41%) had abnormal scans. Two types of abnormalities were observed: high-intensity rounded lesions, > 3 mm in diameters, distributed in the periventricular white matter (leukoaraiosis) in four patients; and cortical atrophy in five patients. Five patients in group B had cortical atrophy, whereas no patient in group A demonstrated this feature (P < 0.05). MRS of the frontal and parietal lobes showed no differences in the N-acetyl aspartate/creatine or N-acetyl aspartate/choline ratios between groups A and B. Patients with cortical atrophy showed a nonsignificant trend toward reduced performance on Rapid Visual Information Processing.

CONCLUSIONS: Brain abnormalities demonstrated by MRI are common in patients with IDDM of long duration and are suggestive of premature aging of the brain. IDDM per se may be an important pathogenic factor, but a significant association was observed between a history of recurrent severe hypoglycemia and cortical atrophy, which may be related to the modest impairment of cognitive function that has been reported previously.

The distribution of hypoglycemic brain damage.

Acta Neuropathol. 1984;64(3):177-91. Auer RN, Wieloch T, Olsson Y, Siesjö BK.

Rats were exposed to insulin-induced hypoglycemia resulting in periods of cerebral isoelectricity ranging from 10 to 60 min. After recovery with glucose, they were allowed to wake up and survive for 1 week. Control rats were recovered at the stage of EEG slowing. After sub-serial sectioning, the number and distribution of dying neurons was assessed in each brain region. Acid fuchsin was found to stain moribund neurons a brilliant red. Brains from control rats showed no dying neurons. From 10 to 60 min of cerebral isoelectricity, the number of dying neurons per brain correlated positively with the number of minutes of cerebral isoelectricity up to the maximum examined period of 60 min. Neuronal necrosis was found in the major brain regions vulnerable to several different insults. However, within each region the damage was not distributed as observed in ischemia. A superficial to deep gradient in the density of neuronal necrosis was seen in the cerebral cortex. More severe damage revealed a gradient in relation to the subjacent white matter as well. The caudatoputamen was involved more heavily near the white matter, and in more severely affected animals near the angle of the lateral ventricle. The hippocampus showed dense neuronal necrosis at the crest of the dentate gyrus and a gradient of increasing selective neuronal necrosis medially in CA1. The CA3 zone, while relatively resistant, showed neuronal necrosis in relation to the lateral ventricle in animals with hydrocephalus. Sharp demarcations between normal and damaged neuropil were found in the hippocampus.

The periventricular amygdaloid nuclei showed damage closest to the lateral ventricles. The cerebellum was affected first near the foramina of Luschka, with damage occurring over the hemispheres in more severely affected animals. Purkinje cells were affected first, but basket cells were damaged as well. Rare necrotic neurons were seen in brain stem nuclei. The spinal cord showed necros is of neurons in all areas of the gray matter. Infarction was not seen in this study. The possibility is discussed that a neurotoxic substance borne in the tissue fluid and cerebrospinal fluid (CSF) contributes to the pathogenesis of neuronal necrosis in hypoglycemic brain damage.

Basal Ganglia

MRI’s of patients subjected to recurrent hypoglycemia

Case 1

MRI of brain - 1/13/03 - showed scattered foci of increased signal

in the periventricular white matter with changes more prominent

on the left. These white matter changes appear to be chronic.

LOCAL PATIENT WITH BRAIN INJURY FROM HYPOGLYCEMIA

Barbara R. Hx of memory loss for 2 years.

Patient experienced multiple hypoglycemic episodes while on oral hypoglycemic agents.

Barbara R.

Barbara R.

Case 4

Patient D.D.

MRI IMPRESSION by Radiologist:1. No acute intracranial abnormality seen.2. Minimal white matter periventricular changes likely related to early small vessel ischemic

disease.3. Mild age-related atrophy.

Patient D.D.

Case 5

Raymond W. 66 y.o. male with chronic atrial fibrillation, peripheral vascular disease, a foot ulcer on right great toe, history of alcoholism, syncope, and recurrent hypoglycemia. He has memory loss and loss of concentration.

HemoglobinA1C history7/12/00 15.2 Glucophage 1000 mg bid. Humulin N 10 units h.s.

11/07/00 7.5

12/18/02 10.3 70/30 insulin bid 15/18. Sliding scale Novolog insulin

4/28/06 10.1

6/07/06 Lantus insulin 25 units daily. Humalog 15 units twice daily.

Current medications: Lantus 35 units daily. Actos 45 mg daily. Starlix 120 tid. (Vytorin 10/20. Cymbalta 30 mg, Diovan 160 mg. Lasix 20 mg, Digitek 125 mcg. K suppl.)

Case 5. Raymond W.

Case 5 R.W.

73 yo female with memory loss , episodes of confusion and unsteady gait. Hearing loss on right. Type 2 Diabetic . Metformin 1000 mg twice daily. + Januvia 100 mg daily. HgbA1c 7.0 BP 195/85. Blanca C.

43 yo male with 23 years of type 1 DM. Novolog insulin through an insulin pump. Frequent hypoglycemic episodes complicated by seizures and two cerebrovascular accidents. These latter

characterized by slow and slurred speech and difficulty swallowing. Blood sugars falling below 60 mg % several times monthly. Complications: renal insufficiency. GFR 36 and below; peripheral neuropathy; erectile impotence; retinopathy. Also has hypertension and dyslipidemia. Chris B.

63 yo female who has had type 2 DM for 20 years. Began insulin in 1994. 8/27/08 HgbA1c 7.6. C/o memory loss. Has hypertension (up to sytolic 210 mm Hg at one time), dyslipidemia, and diabetic peripheral neuropathy. Prior treatment consisted of Lantus insulin 60 units twice daily (!) and Novolog 40 units twice daily, which was

increased from time to time on a “sliding scale” Belva Mc.

74 yo female with 6 mos of DM 2 treated with Glyburide 5 mg daily. Poor memory for 6 years (!) Diagnosed with “dementia”. CC of dizziness and unsteadiness on her feet. HTN (to 150 systolic)

On Coumadin for several episodes of DVT. Additional more pronounced lesions seen on flair sequence at higher levels at mid-ventricular levels bilaterally.

Is there another etiology for these findings or was the culprit Glyburide.? Jean M.

81 yo male with hx of type 2 DM for 5 yrs. Treated with Glypizide 5 mg bid. HgbA1c 6.3 on 1/29/08. HTN to 152 mmHg systolic. Prior hx of “possible CVA’s”. CC “Trouble with balance and

“weakness” in legs x approx. 4 yrs. HDL 49. Chol/HDL 5.2 1/08. Are all the lesions seen due to hypoglycemia or are they “vascular”? Leroy D.

56 yo female who has had type 1 DM for 43 years. Hgb A1c 6.9 Recurrent hypoglycemia with nocturnal diaphoresis in addition to daytime symtoms (fatigue, dizziness, weakness, diaphoresis). Renal failure. eGFR 16.

Cr 2.99 . Prior treatment Lantus 20 units daily with Humalog 5 units before each meal. Maria D.

53 yo male with type 2 DM for 6 yrs. Recurrent hypoglycemia with treatment outlined below, which was given while he was in renal failure. Comatose for over an hour after a severe episode of hypoglycemia (one month before this MRI). He was probably hypotensive for several minuties as he developed acute renal failure and has been on dialysis for about a

month. Medications: Novolog 4 units with breakfast, lunch and dinner

Lantus insulin 45 units every evening at bedtime David C.

A CASE FOR COMPARISON POSITIVE HISTORY BUT NEGATIVE MRI51 yo female with type 2 DM for 32 yrs. Has been on insulin for 3 yrs. Symptomatic hypoglycemia twice daily. Memory impairment for 2 years and episodic confusion (by history). She has renal insufficiency and peripheral neuropathy. On Lantus 152 units daily and Humalog on a sliding scale with averages dose ranging between 25

and 30 units per day. Symlin “20 units” three times daily. Although the history is very suggestive, there are no hyperdense periventricular changes or vascular “cotton

ball” changes to confirm the suspicion of oligodendroglial scarring from recurrent hypoglycemia. Joan Y.

HISTORY IS POSTIVE BUT THE MRI NOT OBVIOUSLY POSITIVE. READ AS NORMAL BY RADIOLOGIST39 yo female with DM 2 for 10 yrs. On insulin for 5 years. C/o loss of memory. Frequent hypoglycemia.

Medications: Lantus 140 units every morningHumalog 10-15 beofre meals. She reduced this to once daily because of frequent lows.

Melissa R.

Transient brain MRI findings of hypoglycemia

Neurol India. 2008 Apr-Jun;56(2):192-4.Click here to read Links Insulinoma: Reversal of brain magnetic resonance imaging changes following resection.

Pakhetra R, Priya G, Jyotsna VP, Seith A, Ammini AC.

Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029, India. vivekapjyotsna@yahoo.com.

Insulinoma presents with myriad manifestations and severe neurological deficit may develop due to delay in diagnosis. We report a lady who presented with Glasgow coma scale of E1 M2 V1, which did not improve after correction of hypoglycemia. There was complete

reversal of neurological deficit and brain magnetic resonance imaging changes of hypoglycemia on follow-up after resection of pancreatic insulinoma. This is the first report

which shows reversal of hypoglycemic changes in MRI after resection of insulinoma. Insulinoma, pre and post surgery provides a model for study of the effect of hypoglycemia

and its improvement after euglycemia.

Nine Type 1 Diabetic Patients with the same HgbA1C of 6.7% Meeting ADA Goal of under 7%

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