Kearns Sayre Syndrome

Sequelae Hypoxic Ischemia Mri

Fig. 3.11. Series of T2-weighted images showing the classic triad of late sequelae of recurrent or prolonged partial hypoxia-ischemia in a preterm neonate: periventricular leukomalacia.There is a periventricular rim of signal abnormality;the ventricles have an irregular border, especially in the trigonum and occipital horns;and there is loss of white matter volume, the sulci in the parietooccipital region abutting the ventricular walls

Fig. 3.11. Series of T2-weighted images showing the classic triad of late sequelae of recurrent or prolonged partial hypoxia-ischemia in a preterm neonate: periventricular leukomalacia.There is a periventricular rim of signal abnormality;the ventricles have an irregular border, especially in the trigonum and occipital horns;and there is loss of white matter volume, the sulci in the parietooccipital region abutting the ventricular walls striatal dysfunction and degeneration in glutaric aciduria type I was demonstrated to be at least partly related to N-methyl-D-aspartate receptor-mediated neurotoxicity of the endogenously accumulating 3-hydroxyglutarate (Kolker et al. 2002).

In methylmalonic academia, as in carbon monoxide intoxication, there is preferential involvement of the globus pallidus. In this disease the selective lesion is due to accumulation of methylmalonate and alter native metabolites. Methylmalonate has been implicated in inhibition of respiratory chain complex II, and it also inhibits the tricarboxylic cycle (Okun et al, 2002).

Preference for the (neo)striatum in CreutzfeldtJakob disease is partly due to the local severe loss of parvalbumin-positive GABA-ergic inhibitory neurons. As in patients with liver failure and hepato-cerebral syndromes, the striatum has a high signal

Fig. 3.12. In Kearns-Sayre syndrome, the subcortical white matter and the globus pallidus are preferentially affected

Fig. 3.12. In Kearns-Sayre syndrome, the subcortical white matter and the globus pallidus are preferentially affected

Kearns Sayre Syndrome

Fig. 3.13. In mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) the lesions have an infarct-like appearance on MR images, as shown on these transverse FLAIR images in a 9-year-old girl, but do not, as a rule, respect vascular territories. (Courtesy of Dr. M.Heitbrink and Dr.B.Wiarda, Department of Radiology, Medical Center Alkmaar,The Netherlands)

Kearns Sayre Syndrome
Fig. 3.14. IR images of a 3-year-old boy with hepatic failure, showing the effects of T1 shortening of the basal ganglia. Because of the T1 shortening, the basal ganglia can no longer be distinguished from the surrounding white matter
Kearns Sayre Syndrome

intensity on both Tr and T2-weighted images. In Creutzfeldt-Jakob disease this could be related to a higher concentration of manganese (Guentchev et al. 1999).

In intoxications with methylene dioxymetham-phetamine (MDMA, or 'ecstasy') the lesions in the globus pallidus are due to severe brain dopaminergic neurotoxicity combined with less severe serotonergic neurotoxicity (Reneman 2001; Ricaurte et al. 2002).

Scholz (1953, 1963) stated that under specific pathophysiological conditions focal ischemic brain injury could be attributed to peculiarities of the vascular anatomy, while in other conditions the pattern of brain damage could only be explained by the unique properties of the cells themselves. One of the most important observations he made was the influence of the nature of the insult on the resulting damage to the CNS. In acute obstruction of cerebral ves

Putamen Adc
Fig. 3.15. Involvement of the basal ganglia is seen in sporadic 'classic' Creutzfeldt-Jakob disease.The putamen and caudate nucleus have a high signal on the T2-weighted image, whereas the globus pallidus has a high signal on the T1-weighted image

Fig. 3.16. In progressive multifocal leukoencephalopathy the white matter is predominantly involved, to a much greater extent than the gray matter.This results in a sharp demarcation of white from gray matter when the lesion abuts the cortex,as shown in these images sels, he found experimentally that "the cerebral and cerebellar cortical layers, especially the Purkinje cells, were destroyed, whereas the shorter the duration of ischemia the greater the possibility for selection to take place and for the innate characteristics of the structures to be expressed in a special pattern of morphological alterations." This, in fact, also seems to be true for other conditions, such as toxic encephalo-pathies and inherited metabolic disorders.

We could add that the "innate characteristics" mentioned by Scholz should not be seen as a static concept, but rather as a condition that is the product of genetic endowment, stage of development, interaction with other structures in neuronal functional circuits, and dependence on their functional activity and the local condition at the time of the insult.

There are several pathophysiological mechanisms that help to explain selective vulnerability of certain brain areas relative to others:

1. Level of activity is an important factor in selective vulnerability. Energy depletion by hypoxia-is-chemia, toxic influences, and metabolic derangements will have the greatest effect on structures with the highest oxygen demand and chemical turnover. Gray matter in adults has a higher level of activity than white matter and will as a rule be damaged first and most severely. In infants, actively myelinating zones have a high activity and are, therefore, liable to damage. In term neonates with acute profound asphyxia, lesions can be seen in primary myelinating zones in the cerebral cortex, subcortical tracts, and basal ganglia (Fig. 3.4).

2. Specific chemical affinity contributes to selective vulnerability. It has been known for a long time that certain areas in the brain are especially liable to damage by certain toxic agents. Hexachloro-phene intoxication involves myelin sheaths exclusively. Hexachlorophene encephalopathy, induced in preterm neonates by washing them for antiseptic reasons with hexachlorophene-containing solutions, causes a myelinopathy with splitting of the myelin lamellae and intramyelinic vacuole formation. Vacuolating myelinopathy in the neonate always has a special distribution,irrespective of its cause, related to the distribution of myelinated versus unmyelinated areas. A clear example is found in maple syrup urine disease. Intoxication with triethyltin, cuprizone, toxic heroin, or poisoned cocaine also leads to myelin splitting and vacuolation. Furthermore, lipophilic substances generally accumulate preferentially in myelin. Organic solvents such as are used by painters lead to irregular, patchy demyelination and can cause so-called house-painter's dementia or an organic psychiatric syndrome. Demyelination, loss of gray-white matter distinction, and signal changes in the basal ganglia have been described in toluene sniffers. Heavy metal poisoning also shows selective affinity for certain brain regions, as seen for example in Wilson disease (neostria-tum, mesencephalon, dentatorubral tracts, nucleus dentatus), lead encephalopathy (cerebellar white matter in adults, cortical neurons in infants and children),and mercury poisoning in Minamata disease (occipital and parietal cortex).

3. Accumulation and/or deficiency of substances have different effects on different areas of the brain. In inborn errors of metabolism, the selection of primary targets and the pattern of spread of the lesions may be influenced by these factors. Differences in selective vulnerability may be explained by differences in residual activity of enzymes in the various cells, in importance of the enzyme function missing, in effects of the accumulation of abnormal breakdown compounds (psychosine in Krabbe disease), in sensitivity to lack of substances that are not formed, and presence of other factors within the cell with synergis-tic or antagonistic effects. It is often very difficult, if not impossible, to define the factors responsible for well-known patterns of selective involvement in inborn errors of metabolism. Shortage of dietary nutrients may also lead to selective damage. Malnutrition of infants in the 1st year of life leads to delayed myelination. Cobalamin deficiency in subacute combined tract degeneration leads to involvement of specific areas in the brain and spinal cord.

4. Patterns of selective vulnerability may be related to distribution of neurotransmitter systems. In some inborn errors of metabolism, some neu-rodegenerative disorders and some toxic-metabolic encephalopathies, selective vulnerability may result from interference with a neurotrans-mitter system. For instance, inborn errors of GABA metabolism have been described that lead to dysfunction of structures in which GABA-ergic neurotransmission is important. In Segawa syndrome, hereditary progressive dystonia with marked diurnal variation, disturbances of dopaminergic neurotransmission cause nigrostri-atal dysfunction. In hyperammonemia, impairment of the neurotransmission by glutamate occurs.

5. The density of synapses for excitatory amino acids determines the sensitivity to adverse effects of these substances. Excitotoxicity due to overstimu lation by excess excitatory amino acids (glutamate and aspartate) has recently been recognized as a final common pathway for inflicting injury upon the CNS. Many conditions can lead to an abnormal accumulation of excitatory amino acids. The preferential distribution of lesions by this mechanism will basically be in areas with the highest density of related receptors.

6. The density of mitochondria and varying percentages of mutated mitochondrial DNA have been suggested as explanations for the selective involvement of CNS structures in mitochondrial encephalopathies. Some reports have linked the percentage of mutated mitochondrial DNA in the basal ganglia in MELAS to local levels of lactate in MRS (Dubeau et al. 2000).

7. Antigen-antibody reactions may be at the root of selective CNS lesions. This is the case in a number of the paraneoplastic and parainfectious lesions of the brain. Antibodies against tumor antigens may, for example, cross-react with similar antibodies on Purkinje cells. Paraneoplastic CNS disorders such as limbic encephalitis and brain stem encephalitis may be caused by this mechanism. In parainfectious disorders, for example those related to Mycoplasma pneumoniae infections, the same mechanism may play a part and lead to myelin damage in patients with acute disseminated encephalomyelitis.

8. Bacterial, viral, or fungal infection may involve specific structures in the brain. For example, progressive multifocal leukencephalitis is an infection of the oligodendrocyte, and thus predominantly involves white matter (Fig. 3.16). In other disorders the porte d'entrée may be responsible for the localization of the lesion, e.g., in herpes simplex encephalitis (Fig. 3.17).

9. Hyper- or hypo-osmolar conditions may cause white matter lesions in specific brain areas. In sodium intoxication in infants, unmyelinated areas appear to be most severely involved, probably because of the lower 'resistance' to the shifts of water. In central pontine myelinolysis the central part of the pons is mainly involved, for unknown reasons.

10. Another important factor is the nature (severity, duration, recurrence) of the noxious event. This can be seen in neonates with perinatal asphyxia. The pattern of brain damage in chronic or recurrent partial hypoxia-ischemia is very different from the pattern observed in acute profound hypoxia-ischemia. Whereas the first leads to periventricular leukomalacia (Fig. 3.11), the second leads mainly to lesions in the basal ganglia, thalamus, and perirolandic cortex (Fig. 3.4).

11. Trans-synaptic degeneration illustrates that the function of the brain depends on functional cir

Perirolandic Cerebral Cortex

Fig. 3.17. Predominant but not exclusive involvement of temporal lobes is seen in herpes simplex infections, shown here in a FLAIR and a Trweighted image with contrast (upperrow) and two trace diffusion-weighted images (b=1000) (lower row).The ADC values in the affected areas are low (-40% relative to normal appearing tissue)

Fig. 3.17. Predominant but not exclusive involvement of temporal lobes is seen in herpes simplex infections, shown here in a FLAIR and a Trweighted image with contrast (upperrow) and two trace diffusion-weighted images (b=1000) (lower row).The ADC values in the affected areas are low (-40% relative to normal appearing tissue)

cuits, so that damage to one part of the circuit influences function, and possibly the structure of other parts of the circuit. This was established long time ago by Guillain and Mollaret for hypertrophic olivary degeneration. The Guillain-Mol-laret triangle consists of the connections of three nuclei: nucleus ruber, nucleus dentatus, and nucleus olivary inferior. Disruption of this circuit by trauma, tumor, or surgery leads to lesions in the inferior olivary nucleus. It is important to recognize this as a product of trans-synaptic degeneration, and not, in tumor cases, as recurrent or multifocal tumor. Another example is substantia nigra degeneration secondary to lesions in the globus pallidus or secondary lesions in the limbic system when one part is affected (Fig. 3.2).

12. In neonates and infants the developmental stage is also of great importance in determination of which areas will be affected by a noxious agent. The patterns of hypoxic-ischemic lesions in preterm and term neonates are well described and show the changes in vulnerability, which depend on developmental factors. Another example is found in several neuronal storage disorders, such as GM1 gangliosidosis, GM2 gangliosidis and neuronal ceroid lipofuscinosis. It is only in the early-infantile onset variants that the cerebral white matter is involved, probably due to a combination of hypomyelination and white matter degeneration. These diseases primarily involve neurons and axons, and later onset variants lead to degeneration of gray matter structures only. However, if the disease has its onset before completion of myelination, the white matter of the CNS is also severely affected. It may be that the complex process of myelin deposition, which requires joint activity and cross-talk of oligoden-drocytes, axons, and astrocytes, is disturbed because of axonal abnormalities. We found evidence for apoptosis of oligodendrocytes in infantile GM1 gangliosidosis, and this may be the primary problem, but it may also be that this is the consequence of the failed collaboration and subsequently in itself a cause for further myelin loss.

Understanding mechanisms of selective vulnerability contributes to the understanding of patterns of cerebral involvement as shown by MRI. On the other hand, MRI gives us insight into patterns of selective vulnerability and into what we understand about them and what we do not. In disorders of quite different origins, some final common pathways may explain similarities in image abnormalities. On the

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