Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Elevated White Matter Lactate

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68.1 Clinical Features

and Laboratory Investigations Leukoencephalopathy with brain stem and spinal cord involvement and elevated white matter lactate (LBSL) is a rare disorder with an autosomal recessive mode of inheritance. The initial development is normal. In some of the patients, independent walking is unstable from the beginning. Motor deterioration starts at a variable age in childhood or adolescence with signs of spasticity and ataxia involving the legs more than the arms. The disease is slowly progressive.

Patients may become wheelchair-dependent in their teens or twenties, but some still walk in their forties.

Manual dexterity also becomes decreased to a variable degree. At neurological examination, most patients have a distal decrease in position and vibration sense. Some patients develop epilepsy with infrequent seizures. Some of the patients have learning problems from early on, but cognitive decline is of late occur- rence. Some patients have more serious disease than others.A striking feature is that some patients experi- ence an episode of more rapid and partially reversible neurological deterioration accompanied by fever fol- lowing minor head trauma.

Somatosensory evoked potentials with stimulation of the tibial and median nerves are delayed or nega- tive. Sensory and motor nerve conduction velocities are normal.

Extensive laboratory investigations have been un- revealing. Only in some of the patients have mild ele- vations of serum or CSF lactate been found on sever- al occasions. However, extensive mitochondrial work- up in fresh muscle tissue has not revealed abnormalities in any of the patients. No mitochondrial DNA mutations have been found.

Presently, the diagnosis is MRI-based. Prenatal diagnosis is unfortunately not possible.

68.2 Pathology

No pathology information is available.

68.3 Pathogenetic Considerations

The disease has an autosomal recessive mode of inheritance, but the genetic defect is unknown.

68.4 Therapy

No specific treatment is available. Supportive care is important.

68.5 Magnetic Resonance Imaging

LBSL has a distinct MRI pattern. The cerebral white matter is involved to a variable extent. In some patients the abnormalities are extensive (Figs. 68.1 and 68.2), in others they are more limited (Figs. 68.6 and 68.9). The white matter abnormalities are progressive over time, with new structures being involved and some white matter atrophy (Fig. 68.2). In all patients, even in the oldest, the U fibers are spared (Fig. 68.1).

In some patients, the cerebral white matter abnormalities are homogeneous (Fig. 68.10), but in most patients the abnormal cerebral white matter has an inhomogeneous, spotty aspect (Figs. 68.1, 68.6, and 68.9). On FLAIR images the white matter abnormalities are also inhomogeneous with spots of lower signal intensity suggestive of focal rarefaction (Fig. 68.5). In the mildest form, there may be a few focal lesions in the cerebral white matter on a back- ground of limited white matter abnormalities, both in extent and degree of signal change (Figs. 68.6 and 68.9). The corpus callosum is involved, almost always

Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Elevated White Matter Lactate

Chapter 68

Fig. 68.1. A 34-year-old lady with LBSL, presently wheelchair- bound. The T2-weighted images (first, second, and third rows) show extensive inhomogeneous signal abnormalities in the cerebral white matter with sparing of the U fibers.The posteri- or part of the corpus callosum is affected, whereas the anteri- or part is spared. Signal changes are also seen in the posterior limb of the internal capsule.Within the midbrain, signal abnormalities are seen in the pyramidal tracts. At the level of the pons, the entire basis, the medial lemniscus, mesencephalic trigeminal tracts, intraparenchymal parts of the trigeminal nerves, and superior cerebellar peduncles are affected bilater- ally. At the level of the medulla, the inferior cerebellar peduncles, the anterior spinocerebellar tracts, the decussation of the medial lemniscus and the pyramids are involved. The cerebellar white matter is diffusely affected. The T1-weighted images (fourth row) show the inhomogeneities in signal intensity of the abnormal white matter with foci of more prominent signal change

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068_Valk_Leukoencephalo 11.04.2005 8:06 Uhr Seite 510

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Fig. 68.1.

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Chapter 68 Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Elevated White Matter Lactate 512

Fig. 68.2.

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Fig. 68.3. Diffusion-weighted images of the same patient as shown in Fig. 68.2 at the age of 19 years. The Trace diffusion- weighted images (first row, b value = 1000) show a high signal intensity of the abnormal white matter.The ADC maps (second

and third rows) show that some areas, in particular rims of lesions, have a low ADC, whereas the remainder of the white matter has a high ADC

Fig. 68.2. These T2-weighted images of a female patient with LBSL were obtained at the ages of 10 years (first and second rows) and almost 20 years (third and fourth rows). The typical abnormalities are present. Over time the supratentorial white matter becomes more atrophic and the abnormalities become less homogeneous. At the level of the midbrain signal abnormalities become visible in the pyramidal tracts and the medi-

al lemniscus. At the level of the pons, bilateral signal changes were seen in the medial lemniscus, mesencephalic trigeminal tract, intraparenchymal part of the trigeminal nerve, and the superior cerebellar peduncle, whereas on follow-up pyramidal tract abnormalities are seen as well. The cerebellar white matter abnormalities were initially subcortical and become diffuse

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more seriously in the posterior part than the anterior part (Figs. 68.1, 68.2, and 68.6), but sometimes the corpus callosum is homogeneously affected through- out. The posterior limb of the internal capsule is also affected (Figs. 68.1, 68.2, 68.5, 68.6, 68.9, and 68.10).

Within the brain stem and spinal cord, the disease in- volves certain tracts selectively. The pyramidal tracts are affected over their entire length extending down- wards through the posterior limb of the internal capsule and the brain stem into the lateral corticospinal

Fig. 68.4. Spinal images obtained in the patient shown in Figs. 68.2 and 68.3. The patient under- went multiple MRI studies in 10 years and the spinal imaging findings were always the same, with signal abnormalities in the dorsal columns and lateral corticospinal tracts over the entire length of the spinal cord

Fig. 68.5. FLAIR images of the patient shown in Figs. 68.2–68.4. These images show that the abnormal white matter is inhomogeneous with areas of lower signal, suggesting focal white matter rarefaction

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tracts of the spinal cord (Figs. 68.1, 68.2, 68.4, 68.8–68.10). Sensory tracts are also affected over their entire length, involving the dorsal columns in the spinal cord, the medial lemniscus through the brain stem up to the level of the thalamus, and the corona

radiata above the level of the thalamus (Figs. 68.1, 68.2, 68.9, and 68.10). The transverse pontine fibers become involved in later stages of the disease (Fig. 68.1). Cerebellar connections are selectively involved, first the superior and inferior cerebellar pe-

Fig. 68.6. Male LBSL patient at the age of 17 years.He has min- imal neurological problems, mainly consisting of minor spasticity of the legs and some bladder dysfunction.The T2-weighted images show diffuse mild signal changes in the periventricular and deep cerebral white matter. There are superimposed focal lesions with more prominent signal change. The spleni-

um of the corpus callosum and posterior limb of the internal capsule are abnormal. At the level of the pons signal abnormalities are seen in the intraparenchymal part of the left trigeminal nerve.There is a small lesion in the superior cerebellar peduncle on the left. At the level of the medulla lesions are seen in the pyramids

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duncles (Figs. 68.1, 68.2, 68.9, and 68.10), and only at a late stage the middle cerebellar peduncles (Fig. 68.1).

The anterior spinocerebellar tracts at the level of the medulla also become abnormal (Fig. 68.1). A remark- able finding is the consistent involvement of the intra-

parenchymal trajectories of the trigeminal nerve and the mesencephalic trigeminal tracts (Figs. 68.1, 68.2, 68.9, and 68.10). The cerebellar white matter may also develop signal abnormalities, first in the subcortical regions (Fig. 68.2) and subsequently spreading in-

Fig. 68.7. Diffusion-weighted images in the same patient as in Fig. 68.6.The Trace diffusion-weighted image (left, b value

= 1000) shows that the focal lesions have a high signal inten-

sity. On the ADC map (middle and right), the focal lesions have a low ADC, whereas the areas of subtle signal change on the conventional images have high ADC values

Fig. 68.8. Spinal images obtained in the patient shown in Figs. 68.6 and 68.7. There are signal abnormalities in the dorsal columns and lateral corticospinal tracts over the entire length of the spinal cord

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wards to involve all cerebellar white matter through- out (Figs. 68.1 and 68.2). The cerebellum becomes atrophic over time.

The white matter abnormalities are progressive over time. Cerebral white matter abnormalities may be present without any abnormality in the brain stem or cerebellum, but at that time the spinal cord already contains signal abnormalities in the lateral and dorsal tracts. Without spinal imaging, an MRI-based diagnosis is not possible in the early or mildest stages of the disease. Over time, the brain stem abnormalities develop, and finally so do cerebellar white matter abnormalities.

A similar MRI pattern has not been described in any other condition; if present, it is diagnostic.

MRS shows a significant decrease in N-acetylas- partate and increase in myo-inositol in the abnormal white matter, suggesting axonal damage or loss

and gliosis, respectively. White matter choline is increased, too, but the increase is minor, suggesting mildly enhanced membrane turnover, possibly myelin loss. White matter lactate is elevated in almost all patients, but to a variable degree. Cortex spectra are normal. A minor increase in lactate in the cortex voxel is probably explained by admixture of both white matter and CSF in the voxel, lactate levels of up to 1.2 mmol/l being normal in the CSF.

Diffusion-weighted imaging in LBSL patients consistently shows high signal in the affected white matter on the Trace diffusion-weighted images (b value = 1000) (Figs. 68.3 and 68.7), most prominently in the focal lesions, with more severe signal change on the conventional images (Fig. 68.7). The ADC maps consistently show a complicated pattern with a mix- ture of high and low ADC values in areas with high signal on the Trace diffusion-weighted images. The

Fig. 68.9. A female 44-year-old LBSL patient with minimal neurological problems. In the periventricular and deep cerebral white matter subtle signal abnormalities are seen with small foci of more prominent signal change. The posterior limb of the internal capsule is affected. At the level of the pons, bilateral abnormalities are seen in the pyramidal tracts, medial lemniscus, superior cerebellar peduncles, and intrapar-

enchymal trajectory of the trigeminal nerve. At the level of the medulla, abnormalities are seen in the inferior cerebellar peduncles and pyramids.The lowest section is through the up- per part of the cervical spinal cord and shows the involvement of the posterior columns and the lateral corticospinal tracts.

Courtesy of Dr. M. Heitbrink and Dr. B. Wiarda, Department of Radiology, Medical Center Alkmaar, The Netherlands

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low ADCs are mainly seen at the border of the white matter abnormalities (cerebral U fibers, peripheral rim of the cerebellar white matter abnormalities, the small focal lesions). The remainder of the abnormal white matter has elevated ADC values. The reason for

this is at present unknown, but it is clear that concepts such as vasogenic edema, cytotoxic edema, and T2

shine-through effects are insufficient to explain these observations.

Fig. 68.10. A 10-year-old boy with LBSL. In this patient the cerebral white matter abnormalities are homogeneous. Courtesy of Dr. S. Blaser, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto