12 Imaging of Inherited and
Acquired Metabolic Brain Disorders
Mauricio Castillo
M. Castillo, MD, FACR
Professor and Chief of Neuroradiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA CONTENTS
12.1 Predominantly White Matter Disorders with Increased Head Size 177
12.1.1 Alexander Disease 177 12.1.2 Canavan Disease 178 12.1.3 Krabbe Disease 178 12.1.4 Mucopolysaccharidoses 180
12.2 Predominantly White Matter Disorders with Normal Head Size 181
12.2.1 Adrenoleukodystrophy 181 12.2.2 Metachromatic Leukodystrophy 181 12.3 Predominantly White Matter Disorders
with Small Head Size 183 12.3.1 Pelizaeus-Merzbacher Disease 183 12.4 Osmotic Myelinolysis 183
12.5 Predominantly Gray Matter Disorders 185 12.5.1 Effects of Liver Failure and
Parenteral Nutrition 185 12.5.2 Bilirubin Encephalopathy 185 12.5.3 Wilson Disease 186
12.5.4 Disorders of Iron Metabolism That May Involve the Brain 187 12.5.5 Hypoglycemia and Hyperglycemia 188 12.6 Disorders Affecting Gray and White Matter 189 12.6.1 Mitochondrial Disorders 189
12.6.2 Amino Acidurias 191 References 192
12.1
Predominantly White Matter Disorders with Increased Head Size
12.1.1 Alexander Disease
This is a very rare disorder also called fi brinoid leu- kodystrophy (van der Knaap et al. 2001). Recently, a heterozygous dominant mutation in the glial fi bril- lary acidic protein has been described. There is no identifi able biochemical defect. Histologic examina-
tion shows Rosenthal fi bers in the brain, ependyma and pia. It is thought that intracellular deposition of these fi bers lead to abnormal functioning of the oligodendrocytes. Arbitrarily it has been divided into infantile, juvenile and adult forms. Macrocephaly is typical and the manifestations include progressive spastic quadriparesis and intellectual failure leading to death (generally all patients die by their teenage years). It generally presents in infancy or adoles- cence and death occurs as early as 3–10 years after diagnosis. Treatment is only palliative. The disease begins in the frontal regions and then extends pos- teriorly, and is seen as areas of high T2 signal inten- sity (Fig. 12.1). The subcortical u-fi bers are initially spared but rapidly become affected. The basal ganglia may also appear swollen initially. Although contrast enhancement was, in the past, thought to be rare, it is now known that it occurs in most patients early in the course of the disease. This contrast enhancement
Fig. 12.1. Alexander disease. Axial T2-weighted image shows abnormal hyperintensity in the deep and superfi cial white matter of the frontal lobes in a symmetrical distribution. (Case courtesy of A. Rossi, Genoa, Italy)
may involve all the areas of abnormal white matter including the basal ganglia. In the end-stage disease, brain cysts may form. This cystic leukomalacia may also show contrast enhancement.
12.1.2
Canavan Disease
Canavan disease (spongiform leukoencephalopathy) is more common in Ashkenazi Jews, and patients gen- erally die 2–3 years after diagnosis (McAdams et al.
1990). Many patients with macrocephaly and imaging fi ndings identical to those of Canavan disease prob- ably have “van der Knaap disease” (van der Knaap et al. 1999). In patients with van der Knaap disease the clinical course is milder and generally only the white matter is diffusely affected. In this disorder, subcorti- cal cysts may be present. Canavan disease is a very rare disorder and is characterized by a defi ciency of the enzyme N-acetylaspartylase [which deacetylates N-acetyl aspartate (NAA) to acetate and aspartate], and therefore proton MR spectroscopy shows mark- edly elevated NAA (Fig. 12.2a). This enzyme is ex- pressed in oligodendrocytes and is involved with the synthesis of myelin lipids. The accumulation of NAA is toxic to the brain and results in myelin splitting (Brismar et al. 1990a). Histologically, there is exten- sive vacuolization (spongy degeneration) of the brain with increased water content. Canavan disease is au- tosomal recessive and the gene encoding for acety- laspartylase is located on chromosome 17. Canavan disease generally begins during the fi rst 6 months of life but there are also congenital and juvenile forms of the disease. Most patients die during the fi rst de- cade of life. There is no effective treatment available.
Canavan disease involves all of the white matter in a diffuse fashion including the sub-cortical U-fi bers (Fig. 12.2b). In addition, the globi pallidi and thalami are nearly always affected (they show high T2 signal).
Much of the affected white and gray matter also show restricted diffusion on diffusion-weighted imaging.
No contrast enhancement is present. As the disease progresses, the size of the head begins to decrease.
Another disease that needs to be included in the differential diagnosis of Canavan disease is Cree leu- koencephalopathy. The imaging fi ndings are identi- cal to those of Canavan but Cree has been reported only in northern Quebec and Manitoba in Canada (Alorayni et al. 1999). Patients with congenital mus- cular dystrophy of the merosin-defi cient type may also present with diffuse increased T2 signal inten- sity in the brain (Fig. 12.2c). These patients, however,
have near normal psychomotor development (com- pared to those with Canavan disease), have muscle weakness of early onset and may have seizures. In both of the previously mentioned disorders, the head size is not enlarged. Diffuse white matter involve- ment may also be seen in the rare “vanishing brain syndrome” (Fig. 12.2d).
12.1.3
Krabbe Disease
This is also a very rare disorder, although in the author’s experience it is perhaps somewhat more common than Alexander and Canavan diseases. It is also called globoid cell leukodystrophy. It is a lysosomal disorder characterized by a defi ciency of the enzyme galactocerebroside beta galactosi- dase, and is inherited as an autosomal recessive trait (Hittmair et al. 1994). The enzymatic defect blocks the degradation of beta galactocerebroside, which is a critical component of the myelin sheaths.
The presence of end products such as psychosine
is toxic to the oligodendrocytes. The diagnosis is
confi rmed by establishing the levels of leukocyte
lysosomal beta galactosidase (Choi and Enzmann
1993). Krabbe disease generally affects infants and
young children, and most patients are diagnosed
between the 3rd and 6th month of life (one of the
earliest leukodystrophies). The head is initially large
and then becomes small (at presentation most pa-
tients are microcephalic). CT may show increased
density in the thalami but, since this study is nowa-
days seldom obtained for patients suspected of hav-
ing leukodystrophies, this fi nding is not commonly
observed (Finelli et al. 1994). MRI shows increased
signal intensity around the ventricles in a non-spe-
cifi c pattern (Hittmair et al. 1994). High T2 signal
may also be seen in the pyramidal tracts and in
the medial aspect of the cerebellar hemispheres. In
the late onset variant, the splenium of the corpus
callosum may be involved. Atrophy ensues in most
patients, particularly late in the disease. The brain
abnormalities generally do not show contrast en-
hancement. Krabbe disease may result in hypertro-
phy of the cranial and spinal nerves (simulating
the fi ndings seen in Guillain-Barrè syndrome) (Lee
et al. 1995). These large nerves may show contrast
enhancement. Bone marrow transplantation may be
helpful in the treatment of the disease. Diffusion
tensor imaging may be the best way to evaluate these
patients. Tensor imaging shows more abnormalities
than T2 weighted imaging and provides a quanti-
Fig. 12.2a–d. Canavan disease and mimics. a Long echo time MR spectroscopy obtained from the white matter shows that the peak of N-acetyl aspartate (2.0 ppm) is markedly elevated. b Axial T2-weighted image in the same child shows diffuse abnormal hyperintensities throughout the white matter and also in the globi pallidi and thalami. c In a child with merosin-defi cient mus- cular dystrophy, axial T2-weighted image shows abnormal signal intensity from the white matter at the level of corona radiata.
d In this child with the vanishing brain syndrome, there is abnormal T2 hyperintensity in all of the white matter 250
200
150
100
50
0
4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 a
b c d
tative measurement of the severity of the disease, making it an optimal way to study the response to therapy.
12.1.4
Mucopolysaccharidoses
This group of disorders also affects the white and the gray matters, and is included here because children may also present with an enlarged head (in reality the diagnosis is well established in most patients by the time of imaging evaluation). They are not true leukodystrophies, but glycosaminoglycans are depos- ited along the perivascular spaces, leading to focal changes mostly in the periventricular white matter.
These compounds are also accumulated inside the cells and are toxic to them. The mucopolysacchari- doses may be considered as disorders of lysosomes (Johnson et al. 1984). Initially there is macrocephaly but progression of these disorders eventually results in brain atrophy. All are inherited in an autosomal recessive fashion, except for Hunter’s disease which is x-linked. The most common mucopolysaccharidoses are Hurler, Morquio, Hunter, while the least common are Sanfi lippo and Maroteaux-Lamy disease. The life span of these patients is variable, but is now improved with the availability of bone marrow transplantation and replacement with recombinant human enzyme (L-iduronidase). The skull is thick and there is doli-
chocephaly and a thick and somewhat keel-shaped frontal bone (these are prominent features in Hurler disease). Expansion of the skull may lead to multiple cranial nerve defi cits. Ventricular dilatation with or without increased intracranial pressure is common (Kumar et al. 1987). It is often very diffi cult to tell whether there is increased intracranial pressure due to the ventricular dilatation. The white matter may show abnormal T2 signal intensity and may contain multiple dilated peri-vascular spaces (Fig. 12.3). It is not clear if these peri-vascular spaces are dilated by the glycosaminoglycans or are part of the spectrum of the communicating hydrocephalus. In the author’s experience, their signal intensity is identical to that of cerebrospinal fl uid in all MR imaging sequences, including FLAIR and DWI. The presence of multiple dilated peri-vascular spaces involving the corpus cal- losum is typical of the mucopolysaccharidoses (in tuberous sclerosis there are multiple dilated peri- vascular spaces, but they almost never involve the corpus callosum and, when they do, they are few and isolated). The cortical sulci may be prominent due to brain atrophy, and occasionally one or more arach- noid cysts are presumably present secondary to the deposition of glycosaminoglycans in the meninges.
Little correlation, however, has been seen by the au- thor between the patient’s clinical defi cits and the imaging fi ndings, that is, the brain may be severely involved but the patient may have only mild clinical manifestations of the disease.
Fig. 12.3a–c. Hunter disease. a Axial T2-weighted image shows dilated perivascular spaces in the posterior periventricular white matter. b Corresponding FLAIR image shows that the lesions are isointense to the cerebrospinal fl uid. c There are also dilated perivascular spaces in the peri-trigonal white matter and in the thalami
b
a c
12.2
Predominantly White Matter Disorders with Normal Head Size
12.2.1
Adrenoleukodystrophy
Adrenoleukodystrophy (ALD) is the most important peroxisomal disorder and one of the most common primary white matter disorders in children. The most common type of these disorders is inherited as an x- linked recessive trait (Xq28) and thus it is only seen in males (Jensen et al. 1990). The neonatal form of ALD is inherited as an autosomal recessive trait and is very rare. Other types of the disease include the ad- renomyeloneuropathy that affects older individuals and the presymptomatic ALD, in which the genetic defect is present but imaging and clinical abnormali- ties are nearly absent. The affected gene in x-linked ALD encodes for the formation of coenzymes derived from the fatty acids within the peroxisomes. This leads to impaired oxidation of fatty acids and their accumulation, which is detrimental to the formation and stabilization of myelin, resulting in active de- myelination and infl ammation. Very long chain fatty acids are not correctly metabolized and become elevated in serum and other tissues. The defect is at the level of the lignoceroyl coenzyme A ligase.
X-linked ALD occurs in boys of 3–10 years of age and a vegetative state or death may occur as soon as 2 years after the diagnosis (Snyder et al. 1991). The most common clinical symptoms are sensorineural hearing loss (90%), pyramidal tract symptoms (50%), visual defi cits (40%), behavioral abnormalities (33%) and seizures (6%). All patients will become vegetative within 5 years of diagnosis. The only hope for cure is early bone marrow transplantation.
In 80% of cases, CT and MRI show abnormalities in the white matter of the occipital regions, also involv- ing the splenium of the corpus callosum and extend- ing anteriorly (Fig. 12.4a). The location of the abnor- malities closely correlates with the symptoms (Loes et al. 1994). Early in the disorder, only the corticospi- nal tracts and/or the medial lemnisci may be affected (Melhem et al. 1996) (Fig. 12.4b). The anterior bor- der of these abnormalities may enhance after contrast administration and this fi nding implies breakdown of the blood–brain barrier due to active demyelin- ation and infl ammation (Fig. 12.4c). Pathologically, the following changes are seen in ALD: zone A (in- ner zone) corresponds to scar and gliosis and shows no contrast enhancement and high T2 signal; zone B
(middle zone) corresponds to infl ammation and de- myelination with axonal preservation and shows con- trast enhancement and high T2 signal intensity; and zone C (outer zone) which has active destruction of myelin but no infl ammation. This latter zone is very thin and is not clearly visualized.
Proton MR spectroscopy obtained at the level of the disease front (zones B and C) shows signifi cant elevation of the choline secondary to the presence of infl ammatory cells. On MR spectroscopy, NAA (a neuronal marker) is decreased, and lactate and lipids (from cellular breakdown) may be elevated (Rajnanayagam et al. 1996, 1997) (Fig. 12.4d). Peaks between 0.9–2.4 may be seen and are believed to be related to the presence of the very long chain fatty ac- ids. Patients with an infl ammatory component have a more rapid and severe course and a worse progno- sis. Diffusion-weighted images may show restriction of water diffusion early in the course of the disease (Fig. 12.4e,f). ALD rarely begins in the frontal regions.
In the chronic stage of the disease, dystrophic calcifi - cations may be seen in the white matter (Barkovich et al. 1994). This fi nding is not only unusual, but it is seldom seen, because CT is no longer commonly obtained in ALD patients.
12.2.2
Metachromatic Leukodystrophy
Metachromatic leukodystrophy (MLD) is a lysosomal disorder that is characterized by a defi ciency in ar- ylsulfatase A (or one of its cofactors) and accumula- tion of sulfatides that are toxic to the white matter (Kim et al. 1997). There is lack of breakdown and reutilization of myelin and the sulfatides impair the function of macrophages and Schwann cells. The presence of sulfatides in urine and defi cient arylsul- fatase A in leukocytes confi rms the diagnosis. It is the most common leukodystrophy and is inherited as an autosomal recessive trait. There is gene mutation in chromosome 22 but this is not present in all pa- tients. Most patients become symptomatic between 1–3 years of age (late infantile form). There is a less common juvenile form in which the patients gener- ally present between 5–7 years of age. Death occurs 1–4 years after diagnosis. Bone marrow transplanta- tion has been tried with varying degrees of success.
On imaging studies, the white matter is diffusely af-
fected but the subcortical u-fi bers are spared (Kim
et al. 1997). The pattern of involvement is periven-
tricular, bilateral and symmetrical (‘butterfl y’ pat-
tern) (Fig. 12.5a). The areas of high T2 signal inten-
b
a c
e f g
d
Fig. 12.4a–g. X-linked adrenoleukodystrophy. a Axial FLAIR image shows increased abnormal signal intensity in the occipi- toparietal white matter and crossing the callosal splenium. b In the same patient, a FLAIR image shows symmetrical hyperin- tensities in the region of the lateral lemnisci. c Post contrast T1-weighted image at same level as (a) shows enhancement of the periphery of the lesions. d MR spectroscopy study obtained with an echo time of 135 ms shows very low NAA, high choline and presence of lactate. e Axial FLAIR image shows location of the voxel used for the MR spectroscopy study shown in (d). f In a different patient, axial trace diffusion-weighted image shows increased signal intensity in the peri-trigonal white matter and in the splenium of the corpus callosum. g In the same patient, there is restricted water diffusion in the region of the right lateral lemniscus
sity may also be somewhat patchy in appearance.
There is no contrast enhancement and the areas of abnormal T2 signal also show abnormal diffusion (Fig. 12.5b). The medial regions of the cerebellum may be involved early in the course of the disease.
Eventually all of the brain (including corpus callosum and brainstem) become involved and atrophy ensues (Stillman et al. 1994).
12.3
Predominantly White Matter Disorders with Small Head Size
12.3.1
Pelizaeus-Merzbacher Disease
Pelizaeus-Merzbacher disease (PMD) is an x-linked disorder (classic form) that is characterized by the lack of myelin specifi c lipids leading to abnormal function of the oligodendrocytes and hypomyelin- ation. It belongs to the group of disorders called
‘sudanophilic’ leukodystrophies (Silverstein et al.
1990). PMD presents very early in life. All of the pa- tients seen by the author presented with abnormal eye movements and cerebral palsy-like symptoms.
The patients also show developmental delay, seizures, spasticity and all die a few years after the initial di- agnosis (Silverstein et al. 1990). The white matter never forms normally due to a defect of the gene that encodes for a ‘proteolipid’ protein, which is essential for the development of myelin. On histology, the white matter has a “tigroid” appearance (van der Knaap and Valk 1989). On imaging studies, the white mat- ter is diffusely abnormal and the brain retains an in utero appearance (the abnormalities may be so dif- fuse and symmetrical that at fi rst glance the studies may even be interpreted as normal) (Fig. 12.6a,b).
There is lack of mature myelin throughout most of the white matter. In the later stages of the disease, the basal ganglia may be dark due to increased iron deposition. The cerebellum may be small and eventu- ally the brain shows atrophy.
Trichothiodystrophy deserves to be briefl y men- tioned here because the brain may show abnormali- ties similar to those seen in PMD on MRI. These pa- tients have ectodermal defects such as brittle hair and abnormal dental enamel (Wetzburger et al. 1998).
In addition to the usual neurological fi ndings seen in most white matter disorders, patients with tricho- thiodystrophy have a peripheral neuropathy and ab- normal hearing. This disease is extremely rare.
12.4
Osmotic Myelinolysis
Osmotic myelinolysis is an acute demyelinating disorder most often seen 2–3 days after the rapid correction of hyponatremia (<15 mmol/L), but may also occur in hypernatremic states or even in the
b a
Fig. 12.5a,b. Metachromatic leukodystrophy. a Axial FLAIR image shows non-specifi c symmetrical periventricular abnor- mal high signal intensity. b In a different patient, axial trace diffusion-weighted image shows abnormal high signal inten- sity throughout the white matter
absence of sodium concentration abnormalities (Ho et al. 1993). It is possible that rapid infl ux of water into the cells associated with sodium alterations re- sults in their damage. The neurological symptoms of hyponatremia may be divided as follows: early stage (anorexia, nausea, vomiting, muscle spasm and weak- ness), advanced stage (impaired responses to verbal commands and pain, bizarre behavior, hallucinations, obtundation, respiratory distress) and severe stage (decortication, bradycardia, hyper- or hypotension,
altered temperature regulation, seizures, respiratory arrest and coma).
Most patients with osmotic myelinolysis are chronic alcoholics, have extensive burns, sepsis, Hodgkin disease, or other malignancies. Osmotic myelinolysis has a high mortality rate, but currently many patients survive. On imaging, most patients show abnormalities in the pontomedullary junc- tion (called ‘central pontine myelinolysis’ or CPM for short) (Sztencel et al. 1983). Histologically, CPM shows acute demyelination (particularly of the pontine transverse fi bers), with preservation of the neurons and axons. Patients with CPM present with lethargy, cranial nerve abnormalities, problems in swallowing, and may progress to quadriparesis, in- cluding a ‘lock in’ syndrome.
Imaging studies are reported as normal in up to 85% of patients with the clinical syndrome of CPM.
MRI shows an area of high T2 signal centered in the lower pons (Korogie et al. 1993; Price et al. 1987) (Fig. 12.7). Sometimes the lesion has a triangular appearance on axial images with its apex located in the midline and pointing forward (pontine infarcts may be triangular-shaped, but the lesion is nearly always off midline and its apex points posteriorly).
In most patients, CPM has a nonspecifi c appearance and involves the entire cross section of the brain- stem. The lesion is devoid of mass effect and con- trast enhancement. Although the cerebellar cortex is affected commonly, this fi nding is not usually appreciated on MRI. In 10% of patients, the supra- tentorial gray matter structures that are surrounded
Fig. 12.6a,b. Pelizaeus-Merzbacher disease. a Axial T2- weighted image at 3 years of age shows diffuse lack of my- elination. b In a different patient, a T1-weighted image shows diffusely low signal intensity from the white matter indicating lack of mature myelin
Fig. 12.7. Central pontine myelinolysis. Axial T2-weighted im- age shows a triangular-shaped area of abnormal high signal intensity in the mid pons
b a
by white matter may be affected (extrapontine my- elinolysis). The regions most commonly affected are the lentiform nuclei and the thalami. Occasionally, supratentorial white matter structures such as the internal capsule and corpus callosum may be in- volved. When the patients survive, a slow and grad- ual decrease in the size of the lesions is noted on follow-up studies, but their lesion does not resolve completely (Rosenbloom et al. 1984).
12.5
Predominantly Gray Matter Disorders
12.5.1
Eff ects of Liver Failure and Parenteral Nutrition
It is well known that hepatic insuffi ciency will lead to abnormalities on brain MR imaging. T1 weighted images show increased signal intensity in the caudate nucleus, tectum (particularly the inferior colliculi), globus pallidus, putamen, subthalamic nucleus, red nu- cleus, adenohypophysis, and substantia nigra (Etsuo et al. 1991). The abnormalities are bilateral, symmetri- cal, and of homogenous signal intensity; there are no corresponding abnormalities on T2 weighted images and CT scans are normal. The MR imaging fi ndings are believed to be due to increased amounts of man- ganese (Mn) and other factors leading to shortening of the relaxation time. Increased plasma levels of Mn may be found in chronic liver failure, patients receiv- ing long-term parenteral nutrition, and occupational toxicity (Krieger et al. 1995). Nearly 95% of Mn is excreted in bile. Manganese is involved in some enzy- matic cell cycles, including superoxide dismutase and glutamine synthetase. Manganese reaches the brain by way of erythrocytes and plasma. Transferrin and albumin are its carriers in plasma. The half-life of blood Mn is 10–42 days, but when it reaches the brain it may remain there for prolonged periods of time.
Astrocytes have specifi c transport systems for Mn.
Manganese is neurotoxic and results in striatal dopa- mine depletion, NMDA excitotoxicity, and oxidative stress (Krieger et al. 1995). Thus, Mn may play a role in the development of hepatic encephalopathy that is clinically characterized by pyramidal and ex- trapyramidal dysfunction, brisk tendon refl exes, and tremors. The concentration of Mn in the pallidus of cirrhotic patients is three-fold higher compared to controls (Pomier-Layrargues et al. 1995). The fre- quency of MR imaging abnormalities in the brain
of cirrhotic patients is approximately 73% (Pomier- Layrargues et al. 1995).
Long-term total parenteral nutrition results in increased T1 signal intensity in the same regions.
These solutions are rich in Mn and lead to develop- ment of neurological symptoms. Once the parenteral nutrition is discontinued, the MR abnormalities may reverse to normal (Fell et al. 1996). The amount of time required for these abnormalities to resolve is not clear, but most do within 1 year after cessation of parenteral nutrition (Mirowitz and Westrich 1992). T1 hyperintensity in the adenohypophysis and dorsal brainstem due to total parenteral nutri- tion may revert to normal 4 months after treatment is discontinued (Okamoto et al. 1998). Similar fi ndings are noted in patients following liver transplantation (Krieger et al. 1995). Although the clinical and im- aging abnormalities are reversible in adults, its long- term effect on the child’s brain is not known.
Other MR techniques may be more sensitive to the effects of liver disease on the brain than just imag- ing. Magnetization transfer contrast ratios are abnor- mal not only in the previously named brain regions but also in the white matter (Iwasa et al. 1999). With liver failure there is an increased proliferation of Alzheimer type II astrocytes in the affected brain re- gions. The etiology for the proliferation of these cells may be hyperammonemia. These cells are character- ized by cytoplasmic hypertrophy and increased wa- ter content. This relatively large amount of water may decrease magnetization transfer by virtue of protein dilution. Repeated episodes of hepatic failure may lead to the development of acquired (non-Wilsonian) hepatocerebral degeneration. The clinical symptoms are permanent and death commonly follows. By imaging, these patients no longer show the typical T1 hyperintensities in the basal ganglia described above for chronic hepatic encephalopathy. Patients with acquired hepatocerebral degeneration show in- creased T2 signal intensity, particularly in the middle cerebral peduncles (Lee et al. 1998). These zones cor- respond to spongiform myelinolytic changes, most likely the sequelae of ischemia. These changes are not secondary to osmotic myelinolysis.
12.5.2
Bilirubin Encephalopathy
Kernicterus is now a rare disorder and most cases
are the result of isoimmunization to Rh factor or
from ABO blood group incompatibility. As such, it
is almost always a disease of neonates (Rorke 1998).
Later in life, most cases are due to genetic, hemato- logic, or liver diseases, such as defects of glucose- 6-phosphate-dehydrogenase, Crigler-Najjar disease, Gilbert disease and in rare cases secondary to breast feeding or severe sepsis. In kernicterus, the liver is unable to conjugate bilirubin. The enzyme uridine- diphosphate glucuronyl transferase does not func- tion well and albumin-bound (insoluble) bilirubin cannot be deconjugated into bilirubin diglucuronide or “water soluble” bilirubin. Initially the child appears hypotonic, then he/she becomes hypertonic, and af- ter approximately 1 week the hypotonia returns. On gross brain examination, there is yellow staining of the globus pallidus, mammillary bodies, subthalamic nuclei, and the indusium griseum. In the brainstem, the substantia nigra and some of the cranial nerve nuclei may be involved (Rorke 1998).
The histological fi ndings are identical to those caused by hypoxia and/or hypoglycemia and refl ect tissue necrosis. Surrounding infl ammatory changes are common. MR imaging has been used to evalu- ate mostly the sequelae of kernicterus (Erbetta et al. 1998). During the chronic stage there is increased T2 signal intensity in the globus pallidus and in the cerebellar dentate nucleus. These structures are also atrophic (Fig. 12.8). Acutely, babies with kernicterus may show increased T1 signal intensity in the basal ganglia without corresponding T2 weighted abnor- malities. I believe that this fi nding is probably related to acute hepatic insuffi ciency and may be similar to that seen in adults with chronic liver disease.
12.5.3
Wilson Disease
Wilson disease is a genetic disorder of copper me- tabolism that is characterized by failure to incorpo- rate copper into ceruloplasmin in the liver, failure to excrete copper by the liver into the bile, and toxic ac- cumulation of copper in multiple organs (Albernaz et al. 1997). The defect has been mapped on chromo- some 13 q14.3. In addition, concentrations of other heavy metals such as zinc, iron, silver, and aluminum are also increased. The genetic defect is localized to 13q 14.3 and several mutations have been described (Albernaz et al. 1997). Most children present with hepatic failure while most adults present with neu- rological symptoms. Accumulation of copper within Descemet’s membrane results in the Kayser-Fleischer rings. Accumulation of copper in the lens results in the rare “sunfl ower” cataracts. Pathologically there is cell loss and cavitation in the lentiform nucleus.
Copper concentration at these sites is markedly in- creased. Other regions involved include the thalamus, subthalamus, red nucleus, substantia nigra, dentate nucleus, and the brainstem. Microscopically, these regions contain large cells with small nuclei (termed Opalski cells) and these are thought to be typical for Wilson disease. Similar to effects of other liver disorders on the brain Alzheimer type II cells are also found in the affect areas. The brain is diffusely atrophic.
MR imaging shows abnormalities even in absence of clinical neurological fi ndings. The paramagnetic effects of copper are visible by MR imaging only in untreated patients (Magalhaes et al. 1994). Basal ganglia lesions are most often bilateral and sym- metrical. The putamina shows striking increase in T2 signal intensity (Fig. 12.9a). This is present to a lesser degree in other deep gray matter structures.
Thalamic lesions are often present but typically spare the dorsomedial nuclei. White matter tracts includ- ing the dentatothalamic, corticospinal, and pontocer- ebellar tracts are commonly involved. The claustrum may show high T2 signal intensity. The midbrain is bright on T2 weighted images with relative sparing of its deep nuclei giving rise to the so-called Panda sign (Albernaz et al. 1997) (Fig. 12.9b). Although it seems attractive to postulate that high copper concen- trations are responsible for the MR imaging fi ndings, this is probably not true. Copper results in T1 and T2 shortening, thus the imaging fi ndings in Wilson dis- ease are probably secondary to spongy degeneration, cavitation, neuronal loss, and reactive astrocytosis.
There is a correlation between the clinical and MR
Fig. 12.8. Effects of liver failure. Axial T1-weighted image shows increased symmetrical signal intensity in the lentiform nuclei
imaging fi ndings. An abnormal appearing striatum correlates with pseudoparkinsonism, an abnormal dentatothalamic tract with cerebellar signs, and an abnormal pontocerebellar tract with pseudopar- kinsonism. The presence of portosystemic shunting may correlate with abnormalities seen in the glo- bus pallidus. The abnormal T2 signal intensity may improve after copper trapping therapy (King et al.
1996). Contrast enhancement is rare but may be seen when patients are receiving treatment with penicilla- mine. Positron emission tomography shows diffusely reduced glucose metabolism particularly marked in the caudate nucleus, frontoparietal cortex, and lenti- form nucleus (van Wassenaer-van Hall et al. 1996;
Engelbrecht et al. 1995). These fi ndings correlate with the severity of the disease and may be reversed following adequate therapy (Hawkins et al. 1987).
12.5.4
Disorders of Iron Metabolism That May Involve the Brain
Although the disorders involving iron metabolism are relatively common (particularly those related to iron defi ciencies), their effects on the CNS are few.
It is well known that anemia related to chronic and debilitating disorders such as AIDS may result in a spine that appears hypointense on T1 weighted MR imaging. This is presumably due to a compensatory mechanism that leads to storage of iron in the bone marrow. The presence of iron results in a diffuse hy- pointense appearance of the bone marrow (Kuwert et al. 1992).
Disorders of iron overload are less common than anemias, but occasionally give rise to interesting, al- beit uncommon, imaging fi ndings. Iron overload oc- curs when the iron-binding capacity of transferrin is exceeded or when an increased catabolism of eryth- rocytes leads to accumulation of iron in the reticulo- endothelial and organ cells. Patients with hereditary hemochromatosis have an increased iron intestinal absorption. In the brain, iron is deposited in the pituitary gland and may give rise to abnormal and low endocrine functions. In these patients adenohy- pophysis may appear as an area of very low or no signal in both T1 and T2 weighted images (Cordato et al. 1998). In a recent article, a ratio of the signal intensity of the pituitary gland to fat was correlated with gland function (Geremia et al. 1989). These au- thors found that reductions in this ratio correlated with hypogonadotropic hypogonadism and higher ferritin levels. In addition, in these patients the
Fig. 12.9a–c. Wilson disease. a Axial FLAIR image shows low signal intensity from the globi pallidi and abnormal high sig- nal intensity from the lateral putamina. b In the same patient, there is abnormal high signal intensity in the peri-aqueductal region in the midbrain. c Long echo time MR spectroscopy shows mildly decreased N-acetyl aspartate
a
c b
liver is damaged and the brain may show fi ndings related to chronic hepatic encephalopathy. African iron overload (Bantu siderosis) is due to increased ingestion of iron and also may lead to liver failure.
Juvenile hemochromatosis is nearly identical to the hereditary type but manifests earlier in life and most patients die young due to heart failure (Sparacia et al. 1999). Transfusional siderosis occurs only after chronic and repeated whole blood transfusions and is more commonly seen in cancer patients and indi- viduals with sickle cell anemia. Aceruloplasminemia is different from Wilson disease (see above) in that ceruloplasmin is completely absent, not just low (Sparacia et al. 2000). Ceruloplasmin has ferroxi- dase action that is partly responsible for the release of iron from many cells. In the absence of cerulo- plasmin, iron accumulates in the basal ganglia and dentate nuclei of the cerebellum, and gives rise to progressive extrapyramidal signs, cerebellar ataxia, and eventually dementia.
Hallervorden-Spatz disease (HS) and Friedreich’s ataxia are also related to iron overload and degen- erative brain disease. Little is known about the bio- chemical abnormalities of HS but it has been linked to an abnormality in chromosome 20p12.3-p13. Large amounts of iron are deposited in the globus pallidus and pars reticulata of the substantia nigra (Sparacia et al. 2000). Iron deposition leads to axonal swelling and decreased myelin thickness. Microscopy demon- strates the presence of abnormal, spherical bodies that contain superoxide dismutase and are believed to be typical for HS. Eventually, these regions of the brain are destroyed. Patients with HS demonstrate dystonia, muscle rigidity, hyperrefl exia, and choreo- athetosis. Mental retardation is variable and death oc- curs 1–2 years after the diagnosis. Because laboratory fi ndings are non-specifi c, the combination of clinical symptoms and imaging fi ndings are used to establish a diagnosis. The fi ndings on CT scanning are non- specifi c and MR is the imaging method of choice.
Initially, only hypointensity (more pronounced on T2 than on T1 weighted sequences) is seen in the glo- bus pallidus. When gliosis ensues, the globus pallidus becomes hyperintense on T2 weighted images but re- mains surrounded by hypointensity. This represents the so-called eye of the tiger sign and is said to be characteristic for HS.
Friedreich’s ataxia (FA) is a rare autosomal re- cessive disorder. It is part of the hereditary ataxic syndromes and will be discussed here because of its possible relation to abnormal iron metabolism.
In 97% of patients it is caused by an abnormality located in chromosome 9, which encodes a protein
called frataxin which has been localized in the mi- tochondria, although its function is unknown (Berg et al. 2000). Increased iron deposition is found in the heart, liver and spleen in a pattern consistent with a mitochondrial location. There is iron accumulation, mitochondrial respiratory chain dysfunction and mi- tochondrial DNA depletion. The spinal cord is patho- logically atrophic with damaged white matter tracts.
The lumbar and sacral nerves are also atrophic. The cerebellar cortex and the brainstem may also show atrophy. Atrophy of the gray matter in the central sulcus is occasionally evident on gross and imaging examinations.
12.5.5
Hypoglycemia and Hyperglycemia
Most cerebral insults due to hypoglycemia occur in young children. Oxygen and glucose are the ma- jor substrates needed for normal brain metabolism and absence of either of both leads to signifi cant injury. Hypoglycemia uncommonly affects the neo- natal brain, which is normally fairly resistant to it.
Acute symptoms of hypoglycemia include jitteri- ness, seizures, and vomiting (Hermann et al. 2000).
Hypoglycemia is diagnosed when the whole blood glucose concentration falls below 20 mg/dl in pre- term babies, 30 mg/dl in term babies, and 45 mg/dl in adults. Sequelae of hypoglycemia are mental re- tardation, spasticity, visual abnormalities, and mi- crocephaly. In neonates, hypoglycemia leads to dif- fuse edema and infarctions. Typically, the occipital regions are affected more severely but the basal ganglia may also be involved (Bradley et al. 2000) (Fig. 12.10). The reason for this is not clear, but it may be related to the fact that in neonates the visual cortex is relatively more mature and metabolically more active than other regions, as during the neo- natal period it experiences intense axonal migration and synaptogenesis (Spar et al. 1994). Other reasons include diffuse hypoxia secondary to heart failure, loss of cerebral vascular autoregulation, and excit- atory toxicity (Aslan and Dinc 1997). Although the gray matter is especially affected, the occipital white matter and posterior thalamus may also be injured.
Chronically, the cortex of the occipital lobes becomes
thin, malacia develops, and these fi ndings correlate
with visual abnormalities. In adults, hypoglycemia
may also induce occipital infarctions in addition to
infarctions elsewhere (which are generally multiple),
laminar necrosis, and transient imaging abnormali-
ties.
Hyperglycemia also has adverse affects on the CNS. Hyperglycemia may lead to increases in cere- bral lactic acid, which may damage the brain primar- ily or worsen the outcome of patients with underlying infarctions. A typical manifestation, and at times the initial one, of hyperglycemia is hemichorea-hemi- ballism (HH). The clinical manifestation of HH are random and fast jerking motion in the distal extremi- ties (chorea) and violent fl inging and kicking, mainly involving the proximal joints (ballismus) (Kinnala
et al. 1999). In these patients, CT shows high den- sity conforming to one lentiform nucleus and the head of the ipsilateral caudate nucleus (Fig. 12.11a).
These regions are of increased signal intensity on MR T1 weighted images, and T2 weighted images are normal or show only slightly high T2 signal intensity (Fig. 12.11b,c). Occasionally, the ipsilateral cerebral peduncle may also show T1 hyperintensity in its an- teromedial region (Kinnala et al. 1999). Hemorrhage and/or calcifi cations have not been reported in HH and the fi ndings are thought to be due to the presence of gemistocytes. MR spectroscopy obtained from the region of T1 signal intensity abnormality demon- strates elevated lactic acid and decreased creatine.
These features have been interpreted as being due to depletion of energy leading to neuronal malfunction.
Although the above described MR abnormalities are fairly typical for HH, they have also been noted in a patient with lupus erythematosus and chorea (Barkovich et al. 1998).
12.6
Disorders Aff ecting Gray and White Matter
12.6.1
Mitochondrial Disorders
Mitochondrial encephalopathies are relatively rare disorders involving a defect in the oxidative respira-
Fig. 12.10. Hypoglycemia. Axial T2-weighted image shows infarctions in the territories of both middle and the left pos- terior cerebral arteries
Fig. 12.11a–c. Hemiballismus, hemichorea in hyperglycemia. a Axial CT image shows increased density in the left basal ganglia.
b In a different patient, axial T1-weighted image shows increased signal intensity in the left putamen. c Corresponding T2- weighted image shows subtle high signal intensity in the same location
b
a c
tory mechanism (usually due to impaired production of adenosine triphosphate) that leads to accumula- tion of lactic acid. Lactic acid may then be detected in serum or in the CSF on laboratory studies or by proton MR spectroscopy (Shan et al. 1998). Although most patients begin to have symptoms during child- hood, some may present when they are adults. Most mitochondrial disorders affect the skeletal muscles and brain and as such most present with weakness and seizures (due to ischemia) (Kashihara et al.
1998). Mitochondrial disorders and organic acidurias share many biochemical and clinical features. The most common mitochondrial disease is MELAS (mi- tochondrial myopathy, encephalopathy, lactic acido- sis, and strokes) that results in large non-territorial cerebral infarctions (including the basal ganglia and thalami) (Castillo et al. 1995) (Fig. 12.12). It more commonly manifests during the second decade of life, and strokes are the result of impaired function of the muscle in the walls of cerebral arteries. Pathologically there is spongy degeneration, neuronal loss, gliosis, and microcystic liquefaction in the affected regions.
MERFF is characterized by myoclonic epilepsy and its imaging fi ndings are identical to those described for MELAS. Leigh disease (subacute necrotizing en- cephalomyelopathy) is due to pyruvate and cyto- chrome C oxidase defi ciencies (Allard et al. 1988).
This disease is usually diagnosed during the fi rst year of life. It produces abnormalities in the basal ganglia,
the periaqueductal gray matter, and the subcortical white matter (Kim et al. 1996) (Fig. 12.13a,b).
Kearns-Sayre syndrome is characterized by ab- normalities in the basal ganglia and in the white matter (which are extensive) (Medina et al. 1990).
The typical clinical fi ndings in these patients are oph- thalmoplegia and cardiac conduction abnormalities.
Pathologically there is capillary proliferation, necro- sis, vacuolization, and demyelination of the affected areas. The MR imaging fi ndings are extensive and in- clude involvement of all deep gray matter structures (high T2 signal intensity) and extensive increased T2 signal in the white matter.
Fig. 12.12. Mitochondriopathy of the MELAS type. Axial trace diffusion-weighted image shows acute infarction confi ned mostly to the left lentiform nucleus
Fig. 12.13a,b. Mitochondriopathy of the Leigh type. a Axial T2-weighted image shows abnormal high signal intensity in all of the white matter and in the medial lentiform nuclei and thalami. b In the same patient, axial trace diffusion-weighted image shows increased signal intensity in the peri-aqueductal region of the midbrain
b a
12.6.2
Amino Acidurias
Although amino acid disorders are not true leukodys- trophies, they affect predominantly the white matter.
In these disorders there is an abnormal formation of proteolipids that are needed to form normal my- elin. The most common disorders in this group are:
phenylketonuria (PKU) (non-specifi c white matter changes and atrophy on MR imaging), maple syrup disease (white matter and basal ganglia shows high T2 signal on MR imaging), homocystinuria (strokes and arterial occlusions on MRI and MRA respec- tively), and glutaric (dilated sylvian fi ssures and in- creased T2 signal in the basal ganglia and thalami), methylmalonic, and propionic acidurias (both show increased T2 signal in the deep gray matter structures and hemispheric white matter) (Paltiel et al. 1987;
Demange et al. 1989; Shaw et al. 1991; Brismar et al. 1990b; Ruano et al. 1998; Brismar and Ozand 1995; Hald et al. 1991). Because of the neonatal screening for PKU mandated by law, this disorder is no longer as severe as it used to be. Patients with PKU are promptly started with a special diet and the imaging fi ndings are mild (Paltiel et al. 1987).
Glutaric aciduria type 1 (type 2 is very rare) is the one that classically results in cyst formation in the regions of the sylvian fi ssures (some believe that these are arachnoid cysts while others believe that they are the refl ection of underlying temporal lobe hypoplasia), white matter abnormalities, and basal ganglia abnormalities (Brismar et al. 1990b; Ruano et al. 1998) (Fig. 12.14a,b). Methylmalonic acidemia results in extensive white matter abnormalities and characteristically high T2 signal intensity in the globi pallidi (Brismar and Ozand 1995; Hald et al.
1991). The fi ndings in propionic aciduria are similar to those seen in methylmalonic aciduria (Brismar and Ozand 1995). Many of these disorders will show a dramatic improvement on MRI after a few weeks of treatment. The myelination milestones are delayed in all of these disorders. Proton MR spectroscopy gener- ally shows several peaks between 1.5 and 2.5 parts per million (ppm) which are thought to represent abnor- mal accumulation of amino acids and low NAA. In my opinion, it is extremely diffi cult to suggest these diagnoses based on imaging fi ndings.
Fig. 12.14a,b. Glutaric aciduria type 1. a Axial CT shows prom- inent sylvian fi ssures and low density from the periventricular white matter and putamina. b Axial T2-weighted image in a different patient shows wide sylvian fi ssures and high signal intensity in the white matter and basal ganglia bilaterally
b a
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