Delayed Posthypoxic Leukoencephalopathy

97.1 Clinical Features

and Laboratory Investigations The usual pathological sequels of hypoxia in the CNS consist of damage to the neurons of the cortex and the subcortical gray matter structures. Selective injury to the cerebral white matter as a consequence of hypox- ia–ischemia occurring in the neonatal period is far less common after hypoxia–ischemia occurring later in life. However, as early as 1925 the German patholo- gist Grinker noticed a diffuse symmetrical leukoen- cephalopathy occurring days after carbon monoxide intoxication. The condition was named after him:

Grinker myelinopathy. As in the original description, posthypoxic leukoencephalopathy may occur imme- diately subsequent to a hypoxic–ischemic insult, but usually there is an early phase of improvement after the initial stage of cerebral injury, followed, several days or weeks later, by recurrence of impaired con- sciousness and other neurological signs. In these cas- es CT and MR show more or less severe leukoen- cephalopathy, and therefore this condition is referred to as delayed posthypoxic leukoencephalopathy (DPHL). The neurological abnormalities in DPHL vary from patient to patient and include spastic pare- sis of the extremities, a parkinsonian syndrome, choreiform movements, visual failure, myoclonus, seizures, psychosis, and mental deterioration. The condition results in a chronic state of global demen- tia, a vegetative state, or death, but recovery may also occur.

The most common cause of DPHL is intoxication with carbon monoxide or cyanide. This may happen accidentally, but also occurs in homicidal or suicidal cases. In the USA not less than 6.4% of suicide at- tempts involve carbon monoxide. This figure is prob- able not far from that in other countries in the west- ern hemisphere.

Laboratory tests in the acute phase include, first of all, determination of blood gases to assess oxygena- tion and acid–base status, since acidosis frequently accompanies the hypoxia. In cases of suspected car- bon monoxide poisoning, the level of carboxyhemo- globin is determined. In carbon monoxide poisoning, the ECG often shows signs of ischemia with inverted T waves and ST wave depression. If other intoxica- tions are suspected, specific laboratory estimations of the level of toxic agents are necessary. The diagnosis of DPHL is established at a later stage with the help of

clinical history, physical findings, and imaging tech- niques. The EEG contains diffuse bilateral slow wave activity with low voltage.

97.2 Pathology

The neuropathological findings are highly variable, depending on the severity and nature of the insult and the time between the event and the pathological examination of the brain. Here only the neuropatho- logical findings of DPHL in the more chronic stage of the disease are described.

The external appearance of the brain is normal or mildly atrophic. On sectioning, confluent white mat- ter lesions are found bilaterally, with a fairly symmet- rical distribution. Microscopically, the central white matter of both hemispheres contains areas of diffuse demyelination with loss of oligodendroglial cells and proliferation of astrocytes. The axons are relatively spared, but areas of extensive necrosis may occur with loss of both myelin and axons. Such necrosis is seen predominantly in arterial end and border zones of the deep white matter, while in the less dis- tant arterial end fields of the white matter only demyelination is observed. The arcuate fibers and white matter underneath the ependyma are better preserved. Patches of myelin persist around numer- ous vessels.

The cortex is usually spared, but concomitant areas of necrosis may be present in the cerebral cortex, especially in an arterial border zone distribution.

Necrotic areas are often present in the basal ganglia.

The brain stem and cerebellum are usually, but not always, unaffected.

97.3 Pathogenetic Considerations

The susceptibility of tissues to anoxic–ischemic dam- age depends on the extent of vascular supply, the presence and quality of collateral circulation, the metabolic activity, and thus the energy demands of the particular tissues. In intoxications the specific chemical affinity and vulnerability of certain brain structures also play a prominent role, as in the initial phase of carbon monoxide poisoning. In the brain anoxic–ischemic processes most commonly affect the cerebral cortex, while the white matter is completely

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or relatively spared. This observation can be ex- plained by the fact that the white matter is metaboli- cally less active than the cortex. Other explanations are found in the distribution of excitatory amino acid synapses and local physicochemical factors at the cel- lular level.

However, a diffuse injury of the white matter is seen in DPHL. DPHL occurs under circumstances of prolonged hypoxia, hypotension, and metabolic im- balance. The underlying causes comprise respiratory failure, cardiac arrest, and systematic hypotension.

Precipitating events are carbon monoxide poisoning, cyanide poisoning, carbon disulfide poisoning, hero- in overdose, morphine intoxication, anesthetic acci- dent, postoperative shock, and many other events.

The white matter lesions of DPHL are located in arterial end and border zones. For their arterial blood supply, the cerebral cortex and arcuate fibers depend on cortical branches of the major cerebral arteries and their leptomeningeal anastomoses. For their supply the periventricular and deep white matter are dependent on penetrating arteries which traverse the brain from the cortex towards the ventricular ependyma. These arteries have few collateral branch- es; one artery nourishes one white matter unit. The basal ganglia receive their supply from end arteries.

The deep white matter lesions of DPHL are frequent- ly accompanied by lesions in the basal ganglia, as well as in border zones of the cerebral cortex. However, there is no clear correlation between gray and white matter damage, and white matter damage does not appear to depend directly on the degree of anoxia.

Although some consider the white matter lesions to be merely a border zone effect, it is probable that something other than hypoxia alone is required for lesions of this kind to be produced. There are several reasons for this assumption. Cerebral DPHL occurs only rarely, in contrast to the much more frequent anoxic–ischemic gray matter damage. In addition, gray matter structures are relatively spared in DPHL, which suggests that the hypoxic–ischemic process in itself is not profound as these structures are rather sensitive to lack of oxygen. This leads to the impres- sion that white matter damage is particularly likely to occur under conditions of prolonged depression of both oxygenation and circulation. Acidosis may be another adverse factor in this context. Drug overdose, for instance morphine intoxication, leading both to a depression of respiration and to hypotension, is par- ticularly apt to lead to DPHL, much more often than, for instance, a cardiac arrest without antecedent im- pairment of respiration.

Carbon monoxide intoxication relatively frequent- ly leads to DPHL. It causes tissue hypoxia by re- versibly binding to hemoglobin in red blood cells, thereby reducing the oxygen-carrying capacity of the blood. The presence of carboxyhemoglobin shifts the

oxyhemoglobin dissociation curve to the left, and tis- sue oxygen tension must therefore fall to much lower levels before the remaining oxyhemoglobin can give up its oxygen, a factor aggravating the tissue hypoxia.

Moreover, carbon monoxide inhibits cellular respira- tion by binding to cytochrome oxidase. In addition to hypoxia, carbon monoxide often causes general hy- potension by the formation of carboxymyoglobin in the myocardium, which in turn leads to myocardial dysfunction. This combination of hypoxia and gener- al circulatory collapse probably explains why DPHL is so often seen in carbon monoxide poisoning.

Cyanide may also lead to DPHL. Cyanides have specific inhibitory effects on the cytochrome oxidase respiratory enzyme system of cells due to a strong affinity of cyanides for the iron core of the cyto- chromes. In this way cyanides lead to tissue hypoxia despite the presence of sufficient amounts of oxygen.

97.4 Therapy

Prevention of cerebral hypoxia and ischemia and the prompt restitution of normal oxygenation, blood pressure, and acid–base balance after any hypoxic–is- chemic insult are the only possible measures in the prevention and treatment of DPHL. The treatment of choice for patients with carbon monoxide poisoning is exposure to hyperbaric oxygen in order to wash out the carbon monoxide as soon as possible. Cyanide poisoning can be treated with hydroxycobalamin and sodium thiosulfate in the acute stage. Adequate treat- ment of the acute poisoning may prevent the occur- rence of DPHL. Once DPHL has developed, the only option is to provide supportive care.

97.5 Magnetic Resonance Imaging

In DPHL, the involvement of the white matter is gen- erally symmetrical and confluent and located in arte- rial border and end zones, due to the underlying sys- temic cause. In carbon monoxide poisoning, exten- sive, confluent deep white matter involvement with late occurrences has been reported, but more focal and asymmetrical white matter involvement has also been observed.

White matter lesions may be accompanied by le- sions in gray matter structures in arterial terminal and border zones of the cortex and in the basal ganglia as the remains of the initial event. In carbon monoxide intoxication, the globus pallidus is pre- ferentially affected. In cases where the original hy- poxic–ischemic encephalopathy had another origin, other gray and white matter structures may also be involved. There are remarkably few reports on imag- ing findings in DPHL. The contribution of MRS is

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described in few articles. Diffusion-weighted Trace images and ADC maps have the possible contribution of distinguishing more recent from older lesions.

97.5 Magnetic Resonance Imaging 757

Fig. 97.1. A 56-year-old man with chronic exposure to carbon disulfide.

The T

-weighted images show nearly symmetrical involvement of the deep white matter. There is also a moderate cerebral atrophy. The basal ganglia and the pons show lesions. From Ku et al. (2003), with permission and cour- tesy of Dr C.C. Huang, Department of Neurology, Chang Gung Memorial Hospital and University, Taipei, Taiwan

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Chapter 97 Delayed Posthypoxic Leukoencephalopathy 758

Fig. 97.2. A 6-year-old boy underwent surgery for a congeni- tal cardiac defect. Postoperatively he did well. Four weeks later he showed behavioral changes. He suffered two cardiac ar- rests,necessitating resuscitation, after which he remained sub- comatose. Neurological recovery was slow and only partial. He

showed signs of spastic tetraplegia. MRI shows extensive changes in the white matter, largely sparing the arcuate fibers.

There are also lesions in the internal capsule,basal ganglia, and mesencephalon. The cerebellum is not affected

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