Nucleus Subthalamicus

> large neurons


Layers 3,5,6> layers 2,4

Vogt (1937) suggested the physico chemical properties of specific neurons as the reason for the unequal vulnerability to disease and introduced the term 'top-istic areas.' The 'pathoclisis' of a region is determined by specific chemical and physical properties, which are also the essence of the specific function of that region. Meyer (1936) stated that it was too simple to assume that only the physicochemical or local vascular factors were involved, and that other factors should also be taken into consideration. Such factors, according to him, are the nature of the noxious agent, the 'porte d'entrée,' the path of distribution, and developmental factors.

Meyer initiated a discussion about the pathophys-iology of the selective involvement of the basal ganglia in some disorders. He drew attention to the selective involvement of the globus pallidus in carbon monoxide intoxication (Fig. 3.1), which is more constant than the involvement of other structures, such as the pars compacta of the substantia nigra, cornu ammonis, Purkinje cell layer of the cerebellum, and

Nucleus Subthalamicus

Fig. 3.1. Carbon monoxide intoxication in a 42-year-old male patient.The T2-weighted images show the hyper-intense lesion in the globus pallidus


Fig. 3.2. Pyruvate dehydrogenase complex deficiency in an 8-year-old boy.The images depict selective involvement of the globus pallidus and the substantia nigra,the latter probably due to transsynaptic degeneration


Fig. 3.3. Kernicterus in a 1-week-old neonate.The upper row shows a proton density and a T2-weighted image at the level of the basal ganglia. The lower row shows a FLAIR and a T1-weighted image at the same level.The images show the typical involvement of the globus pallidus and the pulvinar.The globus pallidus lesions are hardly seen on the T2-weighted image, but the T2-weighted image shows the abnormal signal of the pulvinar more clearly than the other images. It is not completely clear why the globus pallidus has a high signal on the T1-weighted image cerebral white matter. However, the globus pallidus may also be selectively involved in respiratory failure, mitochondrial defects (Fig. 3.2), kernicterus (Fig. 3.3), and intoxications with ether, potassium cyanide, and dinitrobenzol (leading to methemoglobinemia). Meyer, who was well aware of the differences of these conditions, suggested the common factor responsible for the involvement of the globus pallidus was interference with oxygen transport by either severe hypoxia or anemia or 'inhibition of the respiratory en zymes,' showing that awareness of something like the mitochondrial system already existed.

This discussion was renewed recently by Johnston and Hoon (1999), who compared three conditions in children: pyruvate dehydrogenase complex deficiency with a Leigh-like presentation and lesions in the basal ganglia (Fig. 3.2); kernicterus with abnormalities prominently involving the globus pallidus but also involving the nucleus subthalamicus (Fig. 3.3); and posthypoxic-ischemic encephalopathy caused by

Fig. 3.4. T2-weighted series depicting the late pattern of acute profound ischemia in a term neonate.There is a triangular gliosis in the perirolandic white matter, with focal ulegyria of the cortex. In addition, there are lesions in the dorsal part of the putamen, the ventrolateral part of the thalamus, and the dentate nucleus

Acute Profound Asphyxia Basal Ganglia

acute profound asphyxia in a term neonate with basal ganglia abnormalities typically located in the dorsal part of the putamen and the ventrolateral part of the thalamus (Fig. 3.4). The authors try to explain the difference in location of the lesion by arguing that the neuronal circuit involved in asphyxia is different from that involved in mitochondrial disorders and kern-icterus. They suggest that bilirubin toxicity is affecting mitochondria in the globus pallidus, in this way providing a link with mitochondrial respiratory chain disorders. They reason that, on the other hand, glutamate toxicity in particular affects the putamen, thalamus, and cerebral cortex in hypoxic-ischemic conditions.

In an earlier edition of this book (1995) we made the same observation as Johnston and Hoon in 1999: carbon monoxide intoxication affects the globus pal-lidus preferentially and most consistently, whereas hypoxia in cases of near-drowning or strangulation preferentially involves the putamen and caudate nucleus (Figs. 3.5, 3.6), layers 3, 5 and 6 of the cerebral cortex, and Purkinje cells in the cerebellar cortex. In carbon monoxide intoxication we assumed a mito-chondrially mediated effect on the globus pallidus. However, our hypotheses are apparently too simple, and important details of the pathophysiology of the development of brain lesions elude our understand ing. It is a fact, for instance, that in inherited mitochondrial encephalopathies with cellular energy failure the putamen and caudate nucleus are usually preferentially affected and not the globus pallidus (Fig. 3.7). With this observation, it is questionable whether the preferential involvement of the globus pallidus in carbon monoxide intoxications can be blamed on mitochondrial dysfunction.

It is clear that hypoxia-ischemia, some toxic substances, some metabolites increased to toxic levels in inborn errors of metabolism, hypoglycemia, and some nutritional deficiencies (e.g. thiamine deficiency) all interfere with mitochondrial function. In more general terms, regardless of its cause, energy depletion will lead to failure of mitochondrial oxidative phosphorylation,ATP depletion, accumulation of glutamate and other excitatory amino acids, opening of ion channels, accumulation of Ca2+ in the cell, activation of polyunsaturated fatty acid cascades and, finally, cell death. It would be logical if all forms of cerebral energy failure, either caused by hypoxia-ischemia, hypoglycemia, primary mitochondrial dysfunction or deficiencies, intoxications and inborn errors of metabolism mediated through mitochondrial dysfunction, would lead to selective involvement of the same brain structures. This, however, is not true. It is correct that sometimes the pattern of abnormalities

Mitochondrial Resuscitation
Fig. 3.5. A 3-year-old boy suffered near-drowning and prolonged attempts at resuscitation. Not only the striatum is involved, but also the globus pallidus,the thalamus, the hippocampus, and tracts in the brain stem. In addition, cortical laminar necrosis is seen in the higher slices
Near Drowning Brain
Fig. 3.6. A young woman has been anoxic for at least 3 min during resus-citation.The FLAIR images show that the lesions are confined to the striatum

Fig. 3.7. Leigh syndrome in an 8-month-old boy, caused by the Leigh/NARP mutation with a high percentage of heteroplasmy.There are lesions in the putamen and caudate nucleus

Fig. 3.8. Leigh syndrome related to a complex I deficiency in a 3-year-old boy.The MR pattern shows symmetrical lesions in the wall of the third ventricle, the dorsal part of the midbrain, and the dentate nucleus.The mamillary bodies are not affected

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