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57.1 Clinical Features

and Laboratory Investigations Alexander disease (AD) is a rare disorder of the CNS.

Almost all cases are sporadic, but there are occasion- al familial cases with an apparent autosomal dominant mode of inheritance. Three clinical subgroups of AD can be distinguished: infantile, juvenile, and adult.

In infantile AD, the onset of symptoms varies from birth to early childhood. The average age at onset is 6 months. There is increasing macrocephaly together with feeding problems, difficulty swallowing, chok- ing, vomiting, failure to thrive, and signs of neurological deterioration. Slowing down of motor and mental development, loss of acquired developmental mile- stones, spastic quadriparesis, and seizures are usually present. Choreoathetosis and other extrapyramidal signs may occur. In some patients there are clinical signs of elevated intracranial pressure with bulging fontanel, vomiting, and papilledema at funduscopy.

Usually funduscopic findings are normal. Nystagmus and eye movement abnormalities may occur. The children may develop apneic attacks or chronic hy- poventilation. The average duration of the illness is 2–3 years, ranging from a few months to 8 years.

In juvenile AD, the age at onset of clear symptoms varies from 4 to 14 years, with an average age of 9 years. However, in retrospect subtle signs of neurological problems have usually been observed since before the age of 2 years, mainly some developmental delay or seizures. Many of the patients have macrocephaly, but this is a less consistent finding than in infantile AD. The patients suffer from progressive bulbar and pseudobulbar symptoms, with delayed speech development, dysarthria, hoarseness, loss of speech, increasing swallowing problems, and apneic attacks. Many patients have bouts of vomiting, especially during morning hours. The swallowing problems and vomiting often lead to insufficient gain in weight, finally necessitating tube feeding. Spasticity, cerebellar ataxia, seizures, behavioral changes, and cognitive deterioration develop. The average duration of illness is 8 years.

In adult AD, the onset of symptoms is highly variable, occurring between the second and seventh decades. Some of the cases are familial, with an affected parent and one or more affected children. The clinical features reported are highly variable. In some pa-

tients the clinical course is episodic and progressive, as in multiple sclerosis. A chronic progressive course with bulbar and pseudobulbar symptoms, spasticity, cerebellar ataxia, and dementia has been reported.

Nystagmus and other abnormalities in eye move- ments may occur. Some patients only have bulbar signs. Palatal myoclonus may present. Sometimes the disease remains asymptomatic and Rosenthal fibers are found at brain autopsy. Macrocephaly is not a sign of the disease in adults.

Laboratory investigations are not helpful in estab- lishing the diagnosis of AD. CSF is normal or shows a nonspecific increase in protein level. The CSF aB-crystallin level may be elevated, as may be the CSF level of heat shock protein 27 (HSP27), but the sensi- tivity and specificity of these tests have not been as- sessed. High-voltage slow-wave activity and focal dis- charges are recorded on the EEG in most cases, with predominance of abnormalities over the frontal area.

A brain biopsy or autopsy revealing the characteristic Rosenthal fibers used to be considered a prerequisite for a definite diagnosis. However, DNA-based diagnosis is now possible. Sporadic patients are hetero- zygous for a mutation in the GFAP gene which is de novo and not found in one of the parents. In familial cases, affected family members are heterozygous for a mutation in the gene, the disease being transmitted in an autosomal dominant fashion.

57.2 Pathology

In infantile and juvenile AD the brain is abnormally enlarged. External examination may reveal macro- gyria. Olfactory bulbs and optic nerves are sometimes enlarged. In many patients the lateral ventricles are widened, either because of hydrocephalus or because of atrophy and tissue loss. Hydrocephalus, if present, is caused by narrowing of the aqueduct. Oc- casional cases have been reported with a greatly ex- panded cavum septi pellucidi, bulging into the lateral ventricles and compressing the foramina of Monro.

Subependymal cysts may be seen beneath the inferi- or surfaces of both frontal horns. Thalami, basal ganglia, cerebellum, and brain stem may be atrophic on inspection.

On microscopic examination the most distinctive feature of AD is the presence of countless Rosenthal fibers throughout the CNS. Rosenthal fibers are irreg-

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ularly shaped, elongated or round hyaline eosino- philic bodies up to 50 mm in length with a diameter of 1–25 mm. They are arranged radially around blood vessels and perpendicularly to the surface of the cerebral hemispheres, brain stem, cerebellum, and spinal cord in the subependymal and subpial regions. In addition, they are scattered throughout the white matter in all areas of the CNS. Rosenthal fibers are most prominent in the deep frontal white matter, the cerebral cortex, the periventricular region, the basal ganglia, thalami, and brain stem. Deposition of Rosenthal fibers in the cerebellum is variable, being sparse in some cases but prominent in others, involving the cerebellar white matter, dentate nucleus, or, rarely, the subpial layers of the cerebellar cortex. The fornix and optic nerves, chiasm, and tracts may contain many Rosenthal fibers. The peripheral or schwannian parts of the cranial nerves are always free of Rosenthal fibers, whereas the intraparenchymal root bundles may contain heavy deposits. The neurons of the cortex and basal ganglia are usually relatively well pre- served regardless of the degree of Rosenthal fiber deposition, but there may also be a serious loss of neurons in the frontal cortex and deep gray matter structures. In the brain stem the subependymal accumulation of Rosenthal fibers may lead to narrowing of the lumen of the aqueduct, resulting in hydrocephalus.

Throughout the CNS there are accumulations of hypertrophic fibrillary astrocytes, most marked in the subpial, subependymal, and periventricular regions. Their distribution corresponds to the greatest concentration of Rosenthal fibers. The astrocytes are often large and may contain bizarre nuclei. They have large amounts of cytoplasm and, in their perikaryon, hyaline droplets which show the staining characteristics of Rosenthal fibers. On electron microscopy it is evident that the Rosenthal fibers are abundant in astrocytic processes and are present in smaller amounts in the astrocytic perikarya. On electron microscopy Rosenthal fibers appear as irregular, electron-dense, osmiophilic, granular deposits closely associated with intermediate glial filaments. The granular deposits are non-membrane-bound.

Another distinctive histological feature is paucity of myelin. The lack of myelin sheaths is generally most pronounced in the frontal white matter, temporal white matter, centrum semiovale, tegmentum of the brain stem, and ventral and lateral columns of the spinal cord. As a rule the frontal white matter is the most severely involved. There is little or no sparing of the arcuate fibers. The internal capsule, parieto-occipital white matter, and cerebellum are relatively bet- ter myelinated. However, in some cases the cerebellar white matter is also extensively involved. The brain stem involvement may be plaque-like with focal or multifocal areas of myelin paucity. In the areas of

myelin paucity most axons are intact. The affected white matter is markedly cellular due to abundance of abnormal, hypertrophied astrocytes. No inflammatory reaction is present. Oligodendroglia do not show any pathological changes, but may be reduced in number. Cavitation occurs relatively frequently in AD, is usually present in the deep white matter of the frontal lobes, and is sometimes seen in the parietal lobes adjacent to the lateral ventricles and the hilus of the dentate nucleus. In the end stage, the white matter may be severely reduced in volume.

In most cases there is a lack of myelin and at the same time a scarcity of sudanophilic material. Some authors suggest that the absence of typical features of active breakdown of myelin sheaths points to disturbed myelination rather than demyelination. How- ever, in other cases the presence of sudanophilia and macrophages accumulating neutral fat have been reported. Possibly, myelin paucity can be explained by a variable combination of disturbed myelination and demyelination, disturbed myelination being most pronounced in the patients with early onset of disease.

In adult cases, more rarely in juvenile cases, and in exceptional infantile cases, the abnormalities may be much more limited. Usually, brain stem, cerebellar, and spinal cord abnormalities dominate, with Rosen- thal fiber deposits and numerous hypertrophied astrocytes in subpial, subependymal, and perivascular regions. Myelin paucity may be present in the affected areas, but myelin density may also be normal.

There may be focal, tumor-like lesions with mass effect. There may also be a striking atrophy of the lower brain stem and the upper part of the spinal cord.

Microscopy of the lesions may demonstrate prolifer- ated astrocytes with considerable pleomorphism of the nuclei and occasionally multiple nuclei, resem- bling an astrocytoma. The Rosenthal fiber deposition may also be more widespread throughout the CNS.

Likewise, there may be more extensive white matter abnormalities, predominantly involving the frontal and parietal white matter. The white matter involvement may be patchy and multifocal or diffuse. Cavita- tions have been reported in the frontal white matter, but also in the brain stem, hilus of the dentate nucleus, and spinal cord.

57.3 Chemical Pathology

Chemical analysis of brain tissue in AD reveals signs of immature myelin with a relatively high content of glucolipids instead of galactolipids and with a relatively low cerebroside content.All myelin constituents are present in a lower than normal concentration as a consequence of the myelin paucity. Cholesterol esters are not elevated.

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Rosenthal fibers consist of two components: bundles of intermediate filaments, and aggregates of dense material on the filaments. Biochemically, the major proteins of the aggregates are aB-crystallin and HSP27.A fraction of aB-crystallin is ubiquinated.

The filaments contain glial fibrillary acidic protein (GFAP) and vimentin. GFAP is also found in the granular aggregates.

57.4 Pathogenetic Considerations

AD is caused by mutations in the gene GFAP, which encodes GFAP and is, located on chromosome 17q21.

The disease has an autosomal dominant inheritance and almost all patients have a de novo mutation, i.e., which is not found in one of the parents. Familial cases are mainly seen in adult AD, where patients may have offspring. So far, only missense mutations have been found. It is most likely that the mutations ob- served in AD act in a gain-of-function fashion. GFAP- null mice have a subtle phenotype which does not re- semble AD. On the other hand, transgenic mice with overexpression of human GFAP have a fatal en- cephalopathy that closely resembles AD.Astrocytes of these mice are hypertrophic and contain inclusion bodies that are histologically and antigenically iden- tical to Rosenthal fibers. It is not yet known whether defects in other genes may be responsible for some cases of AD.

GFAP is an intermediate filament protein that is expressed almost exclusively in astrocytes of the CNS.

Intermediate filaments are intermediate-sized fi- brous cytoskeletal polymers, which together with smaller actin microfilaments and larger microtubules form the structural framework of the cytoplasm of all eukaryotic cells. GFAP is the major intermediate filament protein of astrocytes. It appears to play a role in the outgrowth of processes of astrocytes. A marked increase in GFAP is part of the complex changes seen in astrocytes after most types of CNS injury. Absence of GFAP leads to surprisingly few change in the un- challenged CNS, but if damage occurs, it is more severe in the absence of GFAP. For instance, experimen- tal allergic encephalitis is more severe in GFAP knock-out mice. On the other hand, accumulation of GFAP in astrocytes apparently leads to a stress re- sponse that induces the small stress proteins aB-crys- tallin and HSP27 and leads to the generation of Rosenthal fibers.

Rosenthal fibers are inclusion bodies composed of intermediate filaments and the small stress proteins aB-crystallin and HSP27. aB-Crystallin and HSP27 are both members of the so-called small heat shock protein family. They are normally present in the brain in small amounts and are water-soluble. The expres- sion of these proteins is enhanced by various stress

conditions. They accumulate in reactive and neoplas- tic astrocytes, and this accumulation is associated with translocation of the proteins from the soluble fraction to the insoluble or cytoskeleton-related frac- tion. In the Rosenthal fibers, aB-crystallin and HSP27 are present as insoluble aggregates bound to interme- diate glial filaments. The association of aB-crystallin and HSP27 with intermediate filaments is probably critical in the formation of Rosenthal fibers. Ubiqui- tin is another component of the Rosenthal fibers.

Rosenthal fibers contain mono- and polyubiquitinat- ed conjugates of aB-crystallin. Conjugation with ubiquitin is the first step in a series of reactions that leads to intracellular nonlysosomal degradation of proteins. However, apparently stable ubiquitin conjugates can also be formed, suggesting that proteolysis is not the only function of ubiquitin conjugation.

Ubiquitin is present in various abnormal filamentous neuronal inclusions, such as the neurofibrillary tan- gles of Alzheimer disease, Lewy bodies in Parkinson disease, and Pick bodies in Pick disease. The presence of ubiquitin in these inclusions may represent an abortive or only partially successful attempt to de- grade proteins that accumulate in the abnormal states mentioned.

The formation of Rosenthal fibers is in itself a nonspecific process. Rosenthal fibers accumulate in glial scar tissue and glial tumors, both of which are conditions characterized by genesis of intermediate filaments. They have been reported as a focal pheno- menon in different types of glial tumors, multiple sclerosis, encephalomalacia, and syringomyelia. More widespread formation has been described in diffuse gliomatosis, central pontine and extrapontine myeli- nolysis, vincristine therapy, radiation therapy, and chronic inflammatory processes. Rosenthal fiber formation appears to reflect chronic pathological processes affecting astrocytes.

There is evidence that myelin paucity is explained at least in part by disturbed myelination. In truly de- myelinating disorders, a macro- and microglial reaction of variable intensity is always found with evidence of phagocytic activity and presence of products of myelin breakdown. In AD, no phagocytic transformation of macroglia and microglia is seen, despite a conspicuous absence of myelin sheaths.

There is a lack of histological and histochemical evidence for the presence of lipoid products of myelin breakdown. There is chemical evidence of a disturbance of myelin maturation. To stress the differences between AD and the regular “myelinoclastic leuko- dystrophies,” the disease has been called a “dys- myelinogenic leukodystrophy.”

The nature of the relationship between astrocytic abnormalities and myelin paucity, whether due to disturbed myelination, demyelination, or both, is un- known. Astrocytes have multiple important func-

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tions. They provide structural support within the ner- vous system, and they play a central role in regenera- tive repair. Astrocytic foot processes provide physical and electrical insulation for synapses. They have an important role in potassium distribution, preventing the accumulation of potassium in the extracellular space during neuronal activity. They are involved in the metabolism of various neurotransmitters, and probably have a reservoir function for nutrients. As- trocytes and their interaction with oligodendrocytes are a prerequisite for oligodendrocyte differentiation and survival and for the deposition and maintenance of myelin sheaths. There are gap junctions between astrocytes and oligodendrocytes, which provide a means of interaction.Astrocytes are the “third factor,”

allowing oligodendrocytes to myelinate axons and to maintain the myelin sheaths already deposited around axons. These data indicate that astrocytic dysfunction in the immature brain of infants, in which myelin is still to be laid down, may have an adverse effect on the process of myelination and myelin maturation, resulting in disturbed myelination and hy- pomyelination. In older patients astrocytic dysfunction may lead to disturbance of myelin maintenance, resulting in demyelination. The reason why certain astrocyte populations are more involved than others is not clear.

The megalencephaly in AD is caused by a combination of astrocytic hyperplasia and massive deposition of Rosenthal fibers. The subsequent atrophy and cyst formation would be secondary to progressive astrocytic cell death in association with loss of other ner- vous tissue components. In neuroimaging the contrast enhancement is seen mainly in the frontal white matter, periventricular rim, basal ganglia, thalamus, hypothalamus, and brain stem, which are the areas with the highest Rosenthal fiber density. The contrast enhancement is probably caused by a defect in the blood–brain barrier related to impaired function to astrocytic foot plates. The Rosenthal fibers are partic- ularly present in astrocytic cell processes and foot plates, and these foot plates form an integral part of the blood–brain barrier.

The topography of the pathological changes correlates with the clinical features. The frontal predominance of the white matter abnormalities correlates with the frequently observed behavioral problems.

Most patients have epilepsy, which correlates with cortical involvement. Bulbar signs are prominent in AD patients, whereas brain stem involvement is almost invariably found in pathology and imaging. It is, however, important to note that in juvenile and adult AD the complete typical imaging picture is already present on early MRI studies obtained during the stage of minimal neurological dysfunction, and that the onset of neurological deterioration may be delayed for many years. Spasticity and ataxia occur usu-

ally relatively late, in the stage of cystic degeneration and atrophy of the white matter.

57.5 Therapy

Treatment is entirely supportive. No causal therapy is available.

57.6 Magnetic Resonance Imaging

In infantile AD, CT discloses bilateral, usually symmetrical, moderately well-demarcated areas of reduced density in the frontal lobes with extensions to the temporal and parietal lobes and the external and extreme capsules. The anterior limb of the internal capsule may be involved. The subcortical arcuate fibers are involved in the process. Temporarily, the white matter abnormalities may show mass effect with compression of the ventricles. A mild to moder- ate enlargement of the lateral and third ventricles ensues, caused either by atrophy or by hydrocephalus due to aqueduct stenosis. In all reported cases, the frontal white matter abnormalities are the most severe, and occipital white matter and cerebellum are completely or relatively spared. However, cerebellar white matter may also become extensively involved.

In many cases a rim of normal or increased density is seen in the subependymal region, including frontal periventricular white matter, caudate nucleus, thalamus, hypothalamus, fornix, and the occipital periventricular white matter (Fig. 57.1). In some cases increased density has also been reported in the subpial cortical layers with a more patchy appearance. Con- trast enhancement is seen in the areas of increased density (Fig. 57.1). Contrast enhancement has also been reported in the dorsal part of the brain stem.

However, some patients show no contrast enhancement, probably depending on the time of examination, because the higher-density enhancing regions decrease as the disease progresses. The course of the disease is characterized by volume loss. Cysts arise in the white matter, especially the frontal white matter, and atrophy ensues. The extent of the white matter abnormalities may increase, but the increase is usually not very prominent. Contrast enhancement is usually absent in late stages of the disease.

In juvenile AD, CT findings include frontal white matter hypodensity. Areas of increased density and contrast enhancement are less prominent than in infantile AD. Over time, white matter atrophy occurs and cysts may form.

In adult AD CT abnormalities limited to the cerebellar white matter and brain stem have been reported. The lesions may be space-occupying.

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In infantile AD, MRI shows abnormal signal intensity of the white matter in a symmetrical distribution with frontal predominance (Figs. 57.2–57.4). The abnormal white matter has usually a swollen aspect, with broadening of gyri and stretching of the overly- ing cortex (Fig. 57.4). However, in infantile cases it may be difficult or impossible to distinguish abnormal white matter from unmyelinated white matter and the frontal predominance may be evident only in the degree of hyperintensity on T2-weighted images or degree of hypointensity on T1-weighted images and the swelling (Figs. 57.2 and 57.3). In some infants there is no evident frontal predominance of white matter abnormalities. There is a characteristic periventricular rim of low signal intensity on T2- weighted images and high signal intensity on T1- weighted images (Figs. 57.2–57.4). There are usually prominent signal abnormalities and swelling of the caudate nucleus, other basal ganglia, and thalamus (Figs. 57.2 and 57.3). These structures may have a high signal on T1-weighted images (Figs. 57.3 and

57.4). In addition, there are usually lesions in the brain stem, most often involving the mid brain and the medulla (Figs. 57.2–57.4). The hilus of the dentate nucleus may have an abnormal signal. The fornix and optic nerves and chiasm may be thickened (Figs. 57.2 and 57.3). Contrast enhancement is often prominent and involves the frontal white matter, ependymal lining of the ventricles, the periventricular rim, the basal ganglia, thalamus, dentate nucleus, brain stem lesions, fornix, and optic chiasm in variable combinations (Figs. 57.2, 57.4, 57.5 and 57.7). The frontal cortex may also show contrast enhancement (Fig. 57.4).

Special features may be hydrocephalus due to aqueduct stenosis and major enlargements of a cavum septi pellucidi and cavum Vergae (Fig. 57.6). Sub- ependymal cysts may be seen at the level of the head of the caudate nucleus. Over time, cavitation of the frontal white matter may occur and may become prominent (Fig. 57.4). Atrophy of the affected white matter, basal ganglia, thalamus, brain stem, and cerebellum occur (Fig. 57.4).

Fig. 57.1. A CT scan without (first row) and with contrast (sec- ond row) in a 4-week-old baby boy with infantile AD. Note the increased density in the frontal white matter, a periventricular rim, and part of the basal ganglia on the images without con-

trast. The same areas enhance with contrast. Courtesy of Dr. S.

Blaser, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, Canada

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57.6 Magnetic Resonance Imaging 421

Fig. 57.2. MRI in the same boy as in Fig. 57.1, a few days later.

The frontal white matter has at most a slightly abnormal signal intensity on the T2-weighted images; its signal intensity is close to normal for unmyelinated white matter. There is a periventricular rim of low signal intensity on the T2-weighted images, most prominent in the frontal region. The head of the caudate nucleus is highly swollen and abnormal in signal. The

fornix is thickened. The midbrain and medulla contain areas of abnormal signal. After contrast (third row), the T1-weighted images demonstrate enhancement of the periventricular rim, frontal white matter, fornix, basal ganglia, and a central area in the thickened optic chiasm. Courtesy of Dr. S. Blaser, Depart- ment of Diagnostic Imaging, Hospital for Sick Children, Toron- to, Canada

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In juvenile AD, there is a frontal predominance of the white matter abnormalities (Figs. 57.8–57.10).

The occipital and temporal white matter may be largely spared, but in some patients only a thin rim of occipital arcuate fibers is spared. The abnormal frontal white matter is usually involved throughout and mildly swollen with some broadening of the gyri.

However, in some patients the white matter changes are restricted to the frontal periventricular region and there is no evident swelling of the abnormal white matter. There is a rim of low signal intensity on T2-weighted images and high signal intensity on T1- weighted images (Figs. 57.8–57.11). The rim is often thin and discontinuous (Figs. 57.8–57.11). There are almost invariably some signal changes in the basal ganglia and thalamus, with some swelling (Figs. 57.8, 57.10 and 57.11). These structures may have a high signal on T1-weighted images (Figs. 57.10 and 57.11).

Very characteristic are the brain stem lesions, most

often seen in the midbrain (in the anterior part, the periaqueductal region, or the entire area except for the red nuclei and the colliculi) and the medulla (either in the central or the posterior part) (Fig. 57.9).

The pontine tegmentum may be involved as well.

Contrast enhancement may involve the frontal white matter, ependymal lining of the ventricles, the periventricular rim, the basal ganglia, thalamus, dentate nucleus, cerebellar cortex, brain stem lesions, and intraparenchymal trajectories of cranial nerves in variable combinations, but the enhancement is as a rule much more subtle than in infantile AD (Figs. 57.9 and 57.10). Over time cavitation of the frontal white matter may occur (Figs. 57.10 and 57.12). The cysts may become very large (Fig. 57.12), but in some patients cysts are never seen. Invariably atrophy occurs of the affected white matter, the basal ganglia, and the thalamus. The atrophic basal ganglia and thalamus have a high, normal, or low signal on T2-weighted

Fig. 57.3. MRI in a 7-week-old baby girl with infantile AD. The frontal white matter has a higher signal intensity than normal for unmyelinated white matter on the T2-weighted images.

There is a rim of low signal on the T2-weighted images and high signal on the T1-weighted images without contrast, ex- tending into the frontal white matter.The caudate nucleus and

putamen have an abnormal signal intensity and are swollen.

The thalamus and large parts of the midbrain have an abnormal signal. The fornix is thickened. From van der Knaap et al.

(2001), with permission; additional images courtesy of Dr. S.

Springer, Department of Pediatrics, Ludwig Maximilian Univer- sity, Munich, Germany

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Fig. 57.4. The same girl as in Fig 57.3, now 3 months old. The first and second rows show the T2-weighted images (left), T1- weighted images without contrast (middle) and with contrast (right).The third row shows T2-weighted images at lower levels.

The frontal white matter now displays much more prominent signal abnormalities and has a swollen appearance. There are small cysts in the frontal white matter. The lateral ventricles have become much wider, probably due to a combination of white matter volume loss and hydrocephalus caused by aqueduct stenosis. The basal ganglia are atrophic and have an ab-

normal signal. There is a thin periventricular rim of low signal on T2-weighted images and high signal on T1-weighted images, which enhances after contrast. Parts of the basal ganglia, frontal white matter and frontal cortex also enhance after contrast. The fornix is thickened and enhances after contrast. The midbrain, hilus of the dentate nucleus, and medulla contain areas of abnormal signal. From van der Knaap et al. (2001), with permission; additional images courtesy of Dr. S. Springer, Department of Pediatrics, Ludwig Maximilian University, Munich, Germany

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Fig. 57.5. T1-weighted images with contrast in a 3-month-old girl (first row) and 6-month-old girl (second row) with infantile AD. The images of the first row show contrast enhancement of spots in the frontal white matter, the basal ganglia, thickened fornix, dorsal part of the midbrain, and ependymal lining.

There is cystic enlargement of the cavum septi pellucidi. The images of the second row demonstrate enhancement of a periventricular rim, basal ganglia, and spots in the brain stem and the colliculi

Fig. 57.6. The T1-weighted sagittal (left) and coronal images (middle and right) of a 4-month-old girl with infantile AD show large frontotemporal cystic areas. The third ventricle is

wide; the cavum septi pellucidi is grossly dilated. Note the small areas of high signal at the frontal horns, frequently seen in AD

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images (Fig. 57.9). The brain stem and cerebellum may also become atrophic. The extent of the white matter abnormalities may increase over time, but the increase is usually not prominent.

MRI is capable of suggesting the diagnosis with a high probability of accuracy, as demonstrated by a high correlation with de novo GFAP gene mutations.

MRI criteria have been defined and four of the five criteria have to be fulfilled for an MRI-based diagnosis.

1. Extensive, symmetrical cerebral white matter abnormalities with a frontal preponderance, either in the extent of the white matter abnormalities, the degree of swelling, the degree of signal change, or the degree of tissue loss (white matter atrophy or cystic degeneration)

2. Presence of a periventricular rim of decreased signal intensity on T2-weighted images and elevated signal intensity on T1-weighted images

3. Abnormalities of the basal ganglia and thalami, either in the form of elevated signal intensity and some swelling or atrophy and elevated or decreased signal intensity on T2-weighted images 4. Brain stem abnormalities, in particular involving

the mid brain and medulla

5. Contrast enhancement involving one or more of the following structures: ventricular lining, periventricular rim of tissue, white matter of the frontal lobes, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, cerebellar cortex, and brain stem structures.

These criteria were designed to facilitate diagnosis in typical AD patients. However, unusual MRI patterns have been reported in DNA-confirmed AD patients, which do not fulfill the above criteria. In exceptional patients, the frontal white matter abnormalities are asymmetrical (Fig. 57.13). A patient with juvenile AD has been reported, in whom cerebellar white changes

Fig. 57.7. T2-weighted images (left),T1-weighted images with- out contrast (middle), and T1-weighted images with contrast (right) in an 18-month-old boy with late-infantile AD. The frontal white matter is abnormal in signal. The basal ganglia and thalami are of mixed signal and are atrophic. There is a periventricular rim with low signal on T2-weighted images and

high signal on T1-weighted images, which enhances after contrast. The rim is double, the inner rim being discontinuous.

Note the small rings at the frontal horns, which enhance after contrast.These small rings are often seen in AD. Courtesy of Dr.

N. Thomas, Department of Pediatric Neurology, Southampton General Hospital, Southampton, UK

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and swelling were most prominent (Fig. 57.14). Over time he also developed frontal white matter changes (Fig. 57.15). Additionally, there are patients, as a rule with juvenile or adult AD, who exclusively or almost exclusively have brain stem, cerebellar, or spinal cord lesions in variable combinations (Figs. 57.16–57.19).

These lesions may be space-occupying, suggesting a multifocal glioma (Figs. 57.18 and 57.19). They are often asymmetrical. These lesions may show contrast enhancement (Figs. 57.15 and 57.17–57.19). Few patients have been reported who only have atrophy of the lower part of the brain stem and upper spinal cord. None of these patients received contrast agent, so that the pattern of enhancement cannot be as- sessed.

The typical AD MRI pattern is quite specific, dis- similar from patterns observed in other white matter disorders. Several leukoencephalopathies share some of the MRI characteristics, but none shares all of them. Predominant involvement of the frontal white

matter together with involvement of diencephalic nuclei and brain stem tracts as well as contrast enhancement may be seen in X-linked adrenoleukodystrophy.

Fig. 57.8. Series of T2-weighted images in a 5-year-old girl with juvenile AD.From these images the ventrodorsal gradient in white matter disease is evident. The basal ganglia have a slightly abnormal signal intensity and a somewhat swollen ap-

pearance.There is a thin periventricular rim of low signal.There are small dark round rings at the frontal horns.The hilus of the dentate nucleus is affected. There are no clear brain stem abnormalities

Fig. 57.9. Series of T2-weighted (first and second rows) and contrast-enhanced T1-weighted images (third and fourth rows) in a 10-year-old boy with juvenile AD.There are extensive cerebral white matter abnormalities with frontal predominance.

There is a thin, discontinuous periventricular rim of low signal on the T2-weighted images. The basal ganglia are atrophic.

There is a lesion in the midbrain and the dorsal medulla. Both the cerebellar hemispheric white matter and the hilus of the dentate nucleus are abnormal, with the dentate nucleus prominently visible in between. After contrast administration there is some enhancement of parts of the ependymal lining of the lateral ventricles, the lesions in the midbrain and medulla, the dentate nucleus, and the cerebellar cortex. From van der Knaap et al. (2001), with permission

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Fig. 57.9.

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However, in this disorder only or mainly the genicu- late bodies are involved among the diencephalic nuclei. The brain stem lesions primarily involve the cor- ticospinal, corticobulbar, visual, and auditory tracts.

Contrast enhancement occurs within the outer bor- der of the white matter lesions. Similarly, some patients with metachromatic leukodystrophy have predominantly frontal white matter abnormalities together with involvement of the brain stem. The brain stem lesions involve the long tracts. Contrast enhancement is not a feature of this disease. Canavan disease is characterized by a combination of macrocephaly, extensive cerebral white matter changes (without frontal preponderance), and basal ganglia abnormalities. However, the thalamus and globus pal-

lidus are typically involved, with sparing of the caudate nucleus and putamen. Contrast enhancement does not occur. In merosin-deficient congenital mus- cular dystrophy, extensive cerebral white matter changes are present with relative sparing of the occipital white matter. However, the basal ganglia and brain stem are spared. In megalencephalic leukoencephalopathy with subcortical cysts, extensive cerebral white matter changes are observed with slight swelling.

However, there are invariably anterior temporal cysts, and often subcortical cysts in the frontoparietal area, whereas the cysts in AD affect primarily the deep frontal white matter. Contrast enhancement is not a feature of megalencephalic leukoencephalopathy with subcortical cysts.

Fig. 57.10. An 8-year-old boy with juvenile AD. The first row contains a T2-weighted image (left) and two T1-weighted im- ages, one without contrast (middle) and one with contrast (right), at the level of the basal ganglia. The second row con- tains T1-weighted images with contrast. Note the extensive cerebral white matter abnormalities with frontal predominance, the periventricular rim with a low signal on the T2- weighted image and high signal on the T1-weighted image,

and the signal abnormalities in the basal ganglia. The fornix is thickened. After contrast administration, enhancement of the periventricular rim, basal ganglia, and frontal white matter is seen. There are cysts of variable size in the frontal white matter. There is a large cavum Vergae. Courtesy of Dr. C. Leite, neu- roradiologist, and Dr. F. Kok, pediatric neurologist, University of São Paulo Medical School, São Paulo, Brazil

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Fig. 57.11. One T2- (left) and one T1-weighted image (right) in a 6-year- old girl with juvenile AD, showing the typical characteristics. Note the high signal of the basal ganglia on the T1-weighted image without contrast

Fig. 57.12. A 7-year-old girl with juvenile AD. Note the huge cysts in the frontal white matter. Note also the periventricular rim of low signal on the T2-weighted image. From van der

Knaap et al. (2001), with permission; additional images courtesy of Dr. S. Naidu, Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, USA

Fig. 57.13. This 5-year-old female with an unusual variant of AD has highly asymmetrical signal abnormalities in the frontal white matter. A brain biopsy was performed to rule out a low- grade glioma; Rosenthal fibers were found. Subsequently, a mutation in the GFAP gene was demonstrated, not present in

her mother (father not investigated). The basal ganglia are mildly abnormal in signal and are mildly swollen, suggestive of AD. There are no brain stem lesions. Courtesy of Dr. N. Thomas, Department of Pediatric Neurology, Southampton General Hospital, Southampton, UK

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Fig. 57.14. A 3-year-old boy with an unusual variant of AD. His cerebellum is highly enlarged, leading to obstructive hydrocephalus for which a ventriculoperitoneal shunt was placed.

The cerebellar white matter is abnormal in signal. He has mild

signal abnormalities in the periventricular white matter, most prominent in the posterior region. A cerebellar biopsy re- vealed Rosenthal fibers and a de novo mutation in the GFAP gene was found

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Fig. 57.15. The same boy as in Fig 57.14, now 12 years old.

He is neurologically remarkably stable. His cerebellum is markedly reduced in size. There are periventricular white matter abnormalities with a frontal predominance.There are slight signal abnormalities in the basal ganglia. The cerebellar white

matter and hilus of the dentate nucleus display prominent signal abnormalities. The medulla contains lesions. After contrast administration, a lesion in the deep parietal white matter, spots in the dentate nucleus, and the dorsal part of the medulla show enhancement

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Fig. 57.16. A 32-year-old patient with adult AD. He had a slowly progressive neurological course and died soon after the MRI. Numerous Rosenthal fibers were found at autopsy and a mutation in the GFAP gene was found, not present in his mother (father not investigated). Most prominent features are

the cerebellar white matter abnormalities and the brain stem atrophy. The lower brain stem is extremely thin. There are also areas of abnormal signal within the brain stem. The contrast- enhanced T1-weighted image (third row, right) shows foci of enhancement in the cerebellum

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Fig. 57.17. An 11-year-old female patient with juvenile AD and a mutation in the GFAP gene.There are minimal supraten- torial abnormalities. Some periventricular white matter abnormalities are seen, most pronounced at the frontal horns. The basal ganglia contain slight signal abnormalities. Several small lesions are present in the middle cerebellar peduncle on the

right and in the medulla. After contrast administration, enhancement of the latter lesions is seen. The small rings at the frontal horns also show some enhancement. Courtesy of Dr. R.

Robinson, Department of Pediatric Neurology, Guy’s Hospital, London, UK

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Fig. 57.18. A 14-year-old male patient with juvenile AD and a de novo GFAP mutation.There are no evident abnormalities in the supratentorial white matter.There are extensive multifocal and confluent abnormalities in the midbrain, pons, medulla, and middle cerebellar peduncles with some mass effect of the

middle cerebellar peduncles. The hilus of the dentate nucleus has an abnormal signal. After contrast administration, numerous foci of enhancement are seen. Courtesy of Dr. A. Reddy, De- partment of Hematology/Oncology, Children’s Health System, Birmingham, Alabama, USA

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Fig. 57.19. A 7-year-old boy with juvenile AD. He had Rosen- thal fibers at histological examination and a de novo mutation in the GFAP gene. Apart from a mild dilatation of the lateral ventricles and a thickened fornix, the T2-weighted images do not show supratentorial abnormalities, neither in the white matter nor in the basal ganglia. There are multiple nodular lesions in the brain stem and middle cerebellar peduncles.The

pons is mildly atrophic. After contrast, enhancement of the fornix and the nodular lesions in the posterior fossa is seen.

Courtesy of Dr. L. González Gutiérrez-Solana, Neuropediatrics Unit, Hospital Niño Jesús, Madrid, Spain, and Dr. A. Messing, Department of Pathobiological Sciences, Waisman Center and School of Veterinary Medicine, University of Wisconsin, Madi- son, Wisconsin, USA