Hereditary Diffuse Leukoencephalopathy with Neuroaxonal Spheroids

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70.1 Clinical Features

and Laboratory Investigations Hereditary diffuse leukoencephalopathy with spher- oids (HDLS) is an autosomal dominant progressive disease. The disease was described for the first time in multiple members of a large Swedish pedigree in 1984 (Axelsson et al. 1984). In this family, 17 of 71 subjects from 4 generations were affected. The age at onset varied from 8 to 60 years, with a mean of 36 years.

The age at death was 39 to 89 years, with a mean of 57 years. The time between onset and death varied from 3 months to over 30 years. Some patients rapid- ly developed severe dementia and died within a few months of the onset of symptoms, whereas in oth- ers the course was prolonged with dementia develop- ing over decades. Sporadic cases have also been re- ported.

The predominant clinical manifestations are psychiatric and include depression, anxiety, alcohol abuse, irritability, and aggressiveness. Psychotic symptoms may occur with confusion, delusions, and hallucinations. The most frequent neurological symptoms are dementia, seizures, impaired balance, retropulsion, gait apraxia, spasticity, ataxia, and uri- nary incontinence. Extrapyramidal symptoms may occur with hyperkinesia, chorea, tremor, and oral dyskinesia.

EEG usually shows nonspecific abnormalities with slowing of the background pattern and sometimes paroxysmal changes. The abnormalities often have a frontotemporal predominance. They may be asym- metrical. Routine and metabolic laboratory investiga- tions reveal no abnormalities. The diagnosis is at pre- sent based on histopathological findings.

70.2 Pathology

External examination of the brain shows mild atro- phy of the frontoparietal regions. The thalamus and the rostral part of the caudate nucleus may be mildly reduced in size. The lateral ventricles are moderately enlarged. The corticospinal tracts and the basis of the pons are atrophic. On microscopy, a widespread leukoencephalopathy is found, characterized by a commensurate loss of myelin sheaths and axons and the presence of numerous neuroaxonal spheroids in

the affected white matter. Neuroaxonal spheroids are round to sausage-shaped axonal swellings, which are easily identified with Bielschowsky, Bodian, and anti- neurofilament immunostains. The leukoencephalo- pathy is most severe in the frontal, frontoparietal, and temporal areas and may be mildly asymmetrical. The U fibers are relatively spared. The abnormalities tend to be most pronounced in the white matter below the pre- and postcentral gyri and extend through the pos- terior limb of the internal capsule into the pyramidal tracts of the brain stem. The corpus callosum is vari- ably affected. The abnormal white matter may show vacuolization. Reactive astrocytes and macrophages are present, but no inflammatory cells. The cerebral cortex and basal ganglia are normal and contain no or only a few spheroids.Within the cerebellum, a marked loss of Purkinje cells is seen, but the cerebellar white matter is normal. Electron microscopy of the spher- oids reveals neurofilaments scattered among elec- tron-dense material and mitochondria.

70.3 Pathogenetic Considerations

The homogeneity of the clinical picture and histo- pathological findings strongly suggests that HDLS is a distinct disease entity. The disease has an autosomal dominant mode of inheritance. Isolated cases are probably the result of new mutations. The genetic de- fect and the pathophysiology of HDSL are as yet un- resolved. Considering the more or less commensurate loss of axons and myelin sheaths, the preferential in- volvement of long tracts, and the presence of axonal swellings, it is likely that axons are the primary target of the disease.

Axonal spheroids are pathological findings char- acteristic of the neuroaxonal dystrophies. They occur most often in the context of neuronal degenerative disorders, such as infantile neuroaxonal dystrophy (Seitelberger disease) and Hallervorden–Spatz dis- ease. The combination of leukoencephalopathy and neuroaxonal spheroids in the abnormal white matter is rare. Apart from HDSL, this combination is ob- served in dermatoleukodystrophy with neuroaxonal spheroids (Matsuyama et al. 1978) and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu–Hakola disease). Both disorders are clinically different from HDLS.

Hereditary Diffuse Leukoencephalopathy with Neuroaxonal Spheroids

Chapter 70

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70.4 Therapy

Supportive care is the only therapeutic option.

70.5 Magnetic Resonance Imaging

MR images demonstrate signal abnormalities bilater- ally within the cerebral white matter, most pro- nounced either within the white matter under the pre- and postcentral gyri (Figs. 70.1–70.3) or within the frontal white matter. The signal abnormalities may be patchy or more confluent, and may be sym- metrical or asymmetrical. They are ill-defined. The corpus callosum is thin and may contain areas of ab- normal signal. The signal abnormalities extend downwards through the posterior limb of the internal capsule into the pyramidal tracts of the brain stem (Fig. 70.1). The affected cerebral white matter is atrophic with widening of the lateral ventricles and subarachnoid spaces (Figs. 70.1–70.3). The head of

the caudate nucleus may be flattened. There may be cerebellar atrophy.

The above MRI findings may confirm the diagno- sis within a pedigree with known HDLS. However, the MRI findings in themselves are not specific and do not allow a definite diagnosis. The diagnosis needs to be confirmed by histopathology.

The differential diagnosis of HDLS includes disor- ders with frontal cortical degeneration, such as fron- totemporal dementia and Pick disease. In these disor- ders MRI shows atrophy mainly of the frontotempo- ral areas. Sometimes there are additional white mat- ter changes, which are ill-defined and usually mild. If present, they make differentiation from HDLS diffi- cult.

The differential diagnosis also includes disorders with frontal lobe dysfunction caused by white matter degeneration, such as metachromatic leukodystro- phy, X-linked adrenoleukodystrophy with frontal pre- dominance, Nasu–Hakola disease, Binswanger dis- ease, CADASIL, orthochromatic pigmentary leukody-

70.5 Magnetic Resonance Imaging 527

Fig. 70.1. A 26-year-old female patient with HDSL. This diagnosis was confirmed histopathologically in her father (Fig. 70.2). Note the patchy and asymmetrical abnormalities in the white matter under the central sulcus. The abnormalities

extend downwards into the posterior limb of the internal capsule and the pyramidal tracts in the midbrain. There is a mild cerebral atrophy.From van der Knaap et al.(2000), with permission

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strophy, and adult-onset autosomal dominant leuko- dystrophies. Most disorders can be ruled out by typi- cal clinical, physical, and laboratory findings and neuroimaging differences. Some disorders require histopathological confirmation.

Chapter 70 Hereditary Diffuse Leukoencephalopathy with Neuroaxonal Spheroids 528

Fig. 70.2. A 55-year-old man with HDSL, father of the patient in Fig. 70.1. The diagnosis was confirmed at autopsy. There is serious cerebral atrophy. The white matter abnormalities are most prominent in the tracts under the pericentral cortex.

They are partially confluent,partially multifocal.The abnormalities extend downwards into the posterior limb of the internal capsule. From van der Knaap et al. (2000), with permission 070_Valk_Hereditary 08.04.2005 16:28 Uhr Seite 528

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70.5 Magnetic Resonance Imaging 529

Fig. 70.3. A 38-year-old woman with HDLS.The diagnosis was confirmed at autopsy. There is prominent cerebral atrophy.

There are patchy, multifocal abnormalities in the cerebral

white matter, most prominently in the central tracts. From van der Knaap et al. (2000), with permission