Adult Onset Adrenoleukodystrophy

Findings

Figure 1 and Figure 2: Axial T2 weighted and FLAIR images demonstrate confluent symmetric hyperintensity in the peritrigonal parietoccipital deep white matter, compatible with adult onset X-ALD.


Diagnosis: Adult Onset Adrenoleukodystrophy


Adrenoleukodystrophy is an x-linked inherited disease involving the central nervous system and adrenal cortex. It results from an inability of peroxisomes to oxidize fatty acids. While seen most commonly in young males, it is also known to present in female heterozygotes. In adults, patients present with varying degrees of cognitive impairment, peripheral neuropathy, bladder and sexual dysfunction.

On imaging, "classic" adrenoleukodystrophy will demonstrate bilateral confluent hyperintense areas in the parietoccipital deep white matter on T2WI and FLAIR. If contrast is administered, it is common to see peripheral linear areas of enhancement with a “leading edge”. In AMN, T2 hyperintensity is also common in the spinal tract fibers of the pons, cerebral peduncles, and internal capsule.

Adult onset adrenoleukodystrophy has been broken down into four main subgroups. The first group is referred to as Pure AMN and is the most common subtype. Patients in this group present with thoracic spinal cord atrophy without any focal lesions and a normal brain MR. Clinically they present with spastic paraparesis and bladder dysfunction. The second group is referred to as AMN Type 1, in which MR will demonstrate T2 hyperintensity along the long tracts of the brain, such as the corticospinal, spinothalamic, and auditory pathways. AMN Type 2 demonstrates extension beyond the long tracts and crosses the corpus collosum. These patients deteriorate much more rapidly and this form most accurately fits this case presentation. The fourth type, Adult Cerebral ALD, results in severe lobar white matter involvement with marked cerebral atrophy.

It is important to consider adult onset ALD/AMN in the differential diagnosis of all adult demyelinating disorders, since it is commonly thought of as a pediatric diagnosis and patients are frequently misdiagnosed with multiple sclerosis or ALS. Early recognition can affect prognosis and delay rapidly progressive neurological deterioration.

Confirmation of the diagnosis can be obtained by various laboratory examinations. Patients will demonstrate elevated concentrations of plasma VLCF. Adrenal function testing will show diminished levels of ACTH. Genetic testing can clinch the diagnosis with a mutation of the ABCD1 locus. Treatment subsequently consists of dietary restriction, Lorenzo’s oil, and statins.

Bilateral ectopia lentis

Findings

Figure 1: Axial noncontrast CT of the head at the level of the orbits demonstrates posterior dislocation of both lenses, which now rest dependently in the vitreous. The etiology in this particular patient was repetitive trauma from serial falls.


Diagnosis: Bilateral ectopia lentis


The crystalline lens of the eye is designed to refract the light entering the iris and project/focus it onto the retina. The lens itself contains no vasculature, nerves, or connective tissue. It sits behind the iris and the front of the lens is in contact with the aqueous fluid of the anterior chamber while the posterior surface of the lens is in contact with the vitreous. The lens is held in place by zonular fibers, otherwise known as suspensory ligaments. These fibers connect to the cilliary body around the circumference of the lens.

Subluxation (partial dislocation) or luxation (complete dislocation) of the crystalline lens, otherwise known as ectopia lentis, is caused by dysfunction or disruption of these zonular fibers. Trauma is the most common cause of this disorder. The absence of a traumatic history should prompt consideration of hereditary causes of zonular fiber dysfunction; predisposing conditions include Marfan syndrome, homocystinurea, tertiary syphilis, and Weil-Marchesani syndrome.

Patients will complain of monocular diplopia, markedly decreased visual acuity in the affected eye(s), and/or poor near vision.

Treatment is determined by lens position, with anterior chamber dislocation often being a surgical emergency. As the aqueous humor of the eye flows in the anterior chamber, around the iris from the cilliary body to the canal of Schlemm, this route can become acutely obstructed with anterior dislocation leading to acute glaucoma. The cornea and iris are also at risk for damage. Posterior dislocation may be treated conservatively depending on lens position, but may also lead to uveitis or glaucoma in some cases.

Joubert syndrome

Findings

There is agenesis of the vermis. The interpeduncular fossa is deep. There is a cerebellar cleft. There is prominence and thickening of the superior cerebellar peduncle. There is a bat wing configuration of the fourth ventricle.


Diagnosis: Joubert syndrome


Key points

Joubert syndrome is an autosomal recessive genetic disorder that affects the cerebellum and midbrain. There is agenesis/hypogenesis of the cerebellar vermis and malformation of the midbrain and brainstem.

With poor development of the cerebellar vermis and brainstem, patients can present with ataxia, hypotonia, and hyperpnea. One of the first clinical signs of Joubert is episodic hyperpnea or apnea in an infant. Breathing can reach upwards of 160 breaths/minute. Mild mental retardation is often seen, though some may have normal intelligence. Patient health and growth are usually not affected. Patients with Joubert benefit from physical, occupational, and speech therapy. Infants with respiratory abnormalities require respiratory monitoring.


Radiologic overview of the diagnosis

The initial radiologic manifestations are often seen on fetal ultrasound with increased nuchal lucency being the most apparent finding. Fetal or Brain MR is the best modality to evaluate the presence of Joubert syndrome.

The classic findings are a hypoplastic/aplastic vermis, thick superior cerebellar peduncles, a deep interpeduncular fossa, and an abnormal midbrain. This configuration resembles a molar tooth and is often referred to as the "molar tooth" sign. The fourth ventricle also takes on a bat wing configuration. The midbrain is usually decreased in AP dimension. In this case, there is complete agenesis of the vermis and the molar tooth sign can be seen with thickening of the superior cerebellar peduncles. The corpus callosum and pars intermedia is thickened and may reflect a compensatory response by the brain adapting to the lack of a vermis.

Chronic progressive external ophthalmoplegia

Findings

The extraocular muscles are atrophic and to some degree show fatty replacement. No abnormal enhancement is present. The globes are intact bilaterally. The intraorbital fat appears slightly increased. There is bilateral orbital proptosis with both globes anterior to the interzygomatic line.


Diagnosis: Chronic progressive external ophthalmoplegia


Key points

Chronic progressive external ophthalmoplegia (CPEO) is characterized by slowly progressive paralysis of the extraocular muscles.
Mitochondrial myopathy usually associated with skeletal muscle weakness.
Presents with bilateral, symmetrical, progressive ptosis, followed by ophthalmoparesis months to years later.

Kearns-Sayre syndrome: Related mitochondrial myopathy with CPEO, onset before age 20 years, pigmentary retinopathy, and at least one of the following: cardiac conduction defects, CSF protein of greater than 100 mg/dL, and/or cerebellar syndrome.
KSS can include mental retardation, hearing loss, seizures, short stature, delayed puberty, and various endocrine disorders.
Frequency: Rare. Males=Females.

Imaging studies: MRI, CT, and ultrasound may show thin, symmetrical extraocular muscles in CPEO, in contrast to enlarged extraocular muscles sometimes seen with Graves disease.
Those with KSS and CPEO display a wide spectrum of MRI findings, including normal brain, diffuse atrophy, and T2 prolongation in subcortical cerebral white matter, cerebellar white matter, globi pallidi, thalami, and substantia nigra.
Diagnosis: Muscle biopsy is definitive test but PCR also shown to be conclusive.

Methylamalonic acidemia

Findings

There are oblong areas of hypointense T1, hyperintense T2 signal in the bilateral globus pallidus (Figure 1 and Figure 2). Figure 3 is a FLAIR image which does not demonstrate edema in this region. Figure 4 is a diffusion weighted image which does not show restricted diffusion, essentially excluding acute infarction.


Diagnosis: Methylamalonic acidemia


Inborn disorders of amino acid metabolism may commonly present with vomiting, feeding difficulties, lethargy, dehydration and metabolic acidosis. Neurologic symptoms include seizures, hypotonia, spasticity, developmental delay, mental retardation, and movement disorders often prompting evaluation with MR imaging.

Briefly, isoleucine, valine, methionine, and threonine are normally converted to propionic acid, methylmalonic acid, and succinic acid, the last step of which requires methylmalonyl CoA mutase and a coenzyme, adenosyl cobalamine. A deficiency in either the enzyme or coenzyme, in an autosomal recessive manner, results in the accumulation of methylmalonic acid. This build up results in the inhibition of succinate dehydrogenase; this enzyme facilitates mitochondrial aerobic glucose oxidation. The globus pallidus is particularly sensitive to mitochondrial dysfunction.

Deficiency in methylmalonyl CoA mutase generally produces earlier onset of symptoms and a more severe course with a mean survival time of 1.5 to 6.4 years.

Neuroimaging in these patients ranges from normal, with a subtle MR spectroscopy finding of elevated CSF lactate, to chronic infarction in the globus pallidus. In general, prominence of the ventricles and sulci with delayed white matter myelination may be seen. In our case, the patient was found to have chronic infarctions of the bilateral globus pallidus without additional parenchymal findings. In cases of suspected methylmalonic academia, correlation with genetic studies may be confirmatory.

Pelizaeus-Merzbacher disease

Findings

There is diffuse T2 prolongation within subcortical, deep, and periventricular cerebral and cerebellar white matter with involvement of internal capsules and corpus callosum. There is also involvement of cerebellar peduncles. No enhancement or diffusion restriction.

Differential diagnosis:
- Pelizaeus-Merzbacher
- Metachromatic leukodystrophy
- Adrenoleukodystrophy
- van der Knaap leukoencephalopathy
- Canavan disease


Diagnosis: Pelizaeus-Merzbacher


Pelizaeus-Merzbacher is a rare leukodystrophy which results in abnormal myelin production. The disease is related to the proteolipid protein 1 (PLP1) gene on the X chromosome. The products of this gene constitute about 50% of the mass of CNS white matter and are believed to serve an important structural function in compact myelin. The defect is most commonly a duplication of genetic material which is deleterious to oligodendrocytes.

The frequency is not certain but is conservatively thought to be more than 1 in 500,000. Clinical signs usually include some combination of nystagmus, stridor, spastic quadriparesis, hypotonia, cognitive impairment, ataxia, and tremor. Patients tend to be normocephalic. Nerve conduction tests typically normal (as opposed to most other leukodystrophies). Diagnosis involves clinical history and physical examination, MRI of the brain, and molecular diagnostic tests. Because of the heterogeneity of genetic defects and since females tend to be heterozygous, there is varying severity and clinical course.

No specific cure or treatment for Pelizaeus-Merzbacher disease is known. Medical care is currently limited to supportive care and includes tracheostomy, physical therapy, orthotics, and antispasticity agents, including intrathecal baclofen.


Radiology

There is lack of myelin maturation on T2WI (i.e. white matter is brighter than it should be) and there is minimal myelin maturation on T1WI (i.e. white matter is darker than it should be). Changes may be difficult to identify under 1 year of age due to the normal lack of myelination. There is diffuse involvement without predilection for a specific distribution or sparing of sub cortical U-fibers. There is no enhancement (in contrast to Alexander or X-linked adrenoleukodystrophy). There is no telltale spectroscopy finding (in contrast to Canavan disease which has elevated NAA). There is no diffusion restriction (in contrast to adrenoleukodystrophy). There is no volume expansion of the white matter (in contrast to van der Knaap leukoencephalopathies).

Leigh disease

Findings

Noncontrast axial FLAIR images through the brain demonstrate increased T2 signal hyperintensity within the bilateral putamen and caudate heads as well as in the gray matter structures of the midbrain. Corresponding noncontrast T1-weighted images show decreased signal within the same structures. Follow-up axial FLAIR image one year later demonstrates increased hyperintensity within with putamen and caudate heads indicating progression of disease.


Diagnosis: Leigh disease (subacute necrotizing encephalomyelopathy)


Leigh disease (subacute necrotizing encephalomyelopathy) is a progressive neurodegenerative disorder that results from an inherited (autosomal recessive or X-linked) mutation within mitochondrial DNA. This results in chronic energy deprivation within the CNS leading to necrosis, gliosis, demyelination, spongiosis, and/or capillary proliferation.

Age of onset is usually less than 2 years old, but juvenile and even adult forms exist. Patients may present with a wide variety of neurologic symptoms ranging from muscle weakness, dystonia, vision loss, ataxia, tachypnea, and seizures. Death generally occurs within a few years after symptom onset usually from respiratory failure. Laboratory findings may include elevated CSF lactate.

Imaging characteristically demonstrates symmetric involvement of the putamen with increased T2 signal and decreased T1 signal on MRI. Other gray matter structures may also be involved including the corpus striatum (caudate nucleus and globus pallidus), thalami, periaqueductal gray matter, and other gray matter structures within the brainstem. White matter changes on imaging are atypical but usually manifest as areas of periventricular increased T2 hyperintensity if present. In addition, MR Spectroscopy adds diagnostic value as elevated lactate levels may be seen within the affected structures such as the basal ganglia.

Adrenal leukodystrophy

Findings

Figure 1: Axial non contrast CT demonstrates symmetric low attenuation in the temporal-parietal white matter. Note involvement of the splenium of the corpus callosum.
Figure 2 and Figure 3: Axial T1 and T2 images demonstrate symmetric T1 hypointensity and T2 hyperintensity in the temporal-parietal white matter corresponding to the low attenuation on CT. Note relative sparing of the subcortical U-fibers.
Figure 4: Axial post gadolinium T1 weighted image demonstrates abnormal hypointensity involving the temporal-parietal white matter, with enhancement of the leading edge which represents active demyelination.
Figure 5: MR spectroscopy demonstrates increased choline and decreased NAA, findings that are non specific but consistent with adrenal leukodystrophy. Note the presence of lactate an indicator of necrosis.


Diagnosis: Adrenal leukodystrophy


Adrenal leukodystrophy is a hereditary disorder caused by impaired beta-oxidation of very long chain fatty acids (VLCFA). Various forms exist, each named according to the age of presentation, including neonatal, childhood, adolescent and adulthood. Another variant, in which there is severe involvement of the spinal cord rather than the cerebrum, is termed adrenomyeloneuropathy (AMN).

The disease is caused by a mutation of the ALD gene which codes for a peroxisomal membrane protein. Transport of very long chain fatty acids into the peroxisome is consequently restricted. This results in reduced supply of shorter chain fatty acids within the peroxisome available for synthesis of complex lipids and proteins, which are myelin components.

The defective myelin is more easily broken down by the body’s normal physiologic functioning and the resulting pathophysiologic processes which include a severe inflammatory demyelination that predominates in the cerebral white matter and axonal degeneration that predominates in the posterior fossa and spinal cord.
These processes manifest radiologically as three zones in the cerebral white matter:
- Zone A, a central burned out zone containing only astrogliosis
- Zone B, an inflammatory zone peripheral to the central zone containing perivascular inflammatory cells and demyelination where axons are preserved
- Zone C, site of demyelination without inflammation.

Clinically, patients suffering from the childhood variant of ALD develop normally initially, but then present with behavioral changes and progressive visual, auditory and motor dysfunction between the ages of 4-10. Diagnosis is usually made by laboratory evaluation of very long chain fatty acid levels once there is clinical suspicion. Treatment options are limited and aimed at lowering levels of VLCFA’s through dietary restriction, consumption of Lorenzo’s oil and lovastatin therapy. Bone marrow transplantation has also shown to be of benefit in some cases. Imaging is helpful as an adjunctive tool to evaluate the extent of disease at presentation and to assess for evolution of the disease during treatment.

The classic picture of ALD is that of confluent, bilateral periatrial (parietal-occipital) deep white matter signal abnormality with sparing of the subcortical u-fibers. The pathological basis for the signal abnormality is a combination of demyelination and gliosis. The signal abnormality demonstrates a “leading edge” of enhancement which reflects blood brain barrier breakdown at sites of active demyelination at the margins of the signal abnormality. Calcifications along the trigone have also been noted as late sequelae.

Loes et al. have described five patterns of involvement, which when considered in the context of patient age at presentation, may give a clue to prognosis:
- Pattern 1 describes involvement of the parietal-occipital white matter and splenium and is associated with rapid progression with younger age of presentation and with enhancement.
- Pattern 2 is that of frontal white matter and genu involvement, and has a similar prognosis to that of Pattern 1.
- Pattern 3 is that of corticospinal tract involvement, usually seen in adults and demonstrates slower progression.
- Pattern 4 is that of corticospinal tract involvement associated with abnormality of the cerebellar white matter, which is seen in adolescents and is also associated with slower progression.
- Pattern 5 is that of concomitant frontal and parietal-occipital white matter abnormality, seen mostly in children and having a rapidly progressive course.

Proton MR spectroscopy demonstrates decreased NAA and myo-inositol and increased choline, glutamine, glutamate and lactate. Decreased NAA/Cr and NAA/Ch ratios and increased Ch/Cr ratios are characteristic. The classic imaging findings are virtually pathognomonic with limited differential diagnosis. Another peroxisomal disorder, acyl CoA oxidase deficiency, has similar imaging findings, but the clinical presentation is much different.

Pelizaeus Merzbacher disease (PMD)

Findings

Figure 1: The coronal T2 image from age 5 demonstrates diffuse T2 hyperintensity in the cerebral white matter.
Figure 2, Figure 3, and Figure 4: Coronal T2 images from ages 8, 10, and 15 demonstrate gross stability of white matter signal abnormalities.
Figure 5 and Figure 6: Axial pre- and post- contrast images from age 15 demonstrate no abnormal enhancement in the white matter.


Diagnosis: Pelizaeus Merzbacher disease (PMD)


Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy that is more properly categorized as a dysmyelinating disorder than a demyelinating disease. Demyelinating disorders such as adrenal leukodystrophy usually result from inborn errors in metabolism. Instead, PMD arises from a genetic defect affecting PLP-1, the primary protein in myelin.

The patient in this case was diagnosed with classic PMD which is the most common of the four forms of the disease. Classic PMD is an X-linked recessive disorder that results most frequently from the duplication of the PLP-1 gene. This genetic error causes a diffuse hypomyelination of the cerebral white matter.

Patients with classic PMD present in infancy with nystagmus, spasticity, and other motor problems. Because of this early presentation, cerebral palsy is the most common misdiagnosis for PMD patients as in this patient. As the patient becomes older, cognitive deficits are more conspicuous and further motor deficiencies may arise. The life span of patients with classic PMD is variable with many succumbing in adolescence and early adulthood while some other patients may live into the sixth decade.

The very slowly progressive MRI findings of classic PMD are quite specific for the disease especially when sequential exams are available for comparison. The cerebral white matter usually appears diffusely low in intensity on T1 images. Findings are more striking on T2 images where the hypomyelinated white matter remains diffusely hyperintense. The corpus callosum is notably atrophic. Myelination is usually present in the brainstem, thalamus, and posterior limbs of the internal capsules. Abnormal enhancement is not seen in PMD as opposed to some demyelinating disorders such as adrenal leukodystrophy in which enhancement is seen at the periphery of the active demyelination. In classic PMD, the MRI findings tend to be stable or mildly progressive over years since the primary problem is hypomyelination rather than demyelination.

Vanderknaap disease - Megaloencephalic leukoencephalopathy with subcortical cysts (MLC)

Findings

Figure 1: Subcortical CSF intensity cyst in superior frontal and parietal lobe. Normal cerebellum.
Figure 2: CSF intensity subcortical cyst in superior parietal and anterior temporal lobe.
Figure 3: Diffusely swollen white matter (blue arrow). Preserved gray matter. CSF intensity subcortical cyst in anterior temporal lobe.
Figure 4: Diffusely swollen white matter. Preserved gray matter.
Figure 5: Cavum septum pellucidum. CSF intensity subcortical cyst in superior frontal and anterior temporal lobe. Normal basal ganglia.
Figure 6: Cavum septum pellucidum. CSF intensity subcortical cyst in superior frontal and anterior temporal lobe. Normal basal ganglia.


Diagnosis: Vanderknaap disease - Megaloencephalic leukoencephalopathy with subcortical cysts (MLC)


Vanderknaap disease is newly described rare leukoencephalopathies includes:
- 1. MLC - Megaloencephalic leukoencephalopathy with subcortical cysts
- 2. VWM - Leukoencephalopathy with vanishing white matter
- 3. WML - White matter disease with lactate
- 4. H-ABC- Hypomyelination with atrophy of the basal ganglia(BG) and cerebellum

Megaloencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukoencephalopathy with an autosomal recessive mode of inheritance. The disease is relatively prevalent among Turkish people and in a certain Asian-Indian community, the Agarwal ethnic group.


MRI Features

In MLC the cerebral hemispheric white matter is diffusely abnormal and swollen. There are almost invariably subcortical cysts in the anterior temporal region, often also in the frontal and parietal subcortical regions The cysts are bilateral. The cysts tend to become larger with age and may increase in number. In some patients they become very large, The signal intensity of the contents of the cysts is always similar to that of CSF. Cortical gray matter structures,corpus callosum and basal nuclei are always normal. A patent and enlarged cavum septi pellucidum and cavum vergae are often present.

Similar white matter changes with swelling have been reported in Canavan disease, Alexander disease, L-2-hydroxyglutaric aciduria, and merosin-deficient congenital muscular dystrophy. However, in Canavan disease, as a rule, MRI demonstrates additional involvement of the thalamus and globus pallidus, not found in MLC patients. Special MRI findings in Alexander disease are a more prominent sparing of parieto-occipital white matter and often also sparing of the U fibers throughout. Basal ganglia and brain stem structures are typically involved. Cavitation starts in the deep frontal white matter. None of these features is present in MLC. In L-2-hydroxyglutaric aciduria MRI shows additional involvement of caudate nuclei, putamen, dentate nuclei, and severe atrophy of the cerebellar vermis, not observed in MLC. The MRI abnormalities observed in merosin-deficient congenital muscular dystrophy are very similar to those observed in MLC.

Glutaric aciduria type I

Findings

There is diffuse cerebral volume loss (atrophy) with dilated bilateral Sylvian fissures and old bilateral putamenal infarcts. In addition, there is increased T2 signal intensity throughout the subcortical white matter without restricted diffusion.

Differential diagnosis:
- Remote trauma or non-accidental trauma
- Glutaric aciduria type I
- Bilateral middle cranial fossa arachnoid cysts
- Mucopolysaccharidoses (types I-VII, Hurler)
- Canavan disease


Diagnosis: Glutaric aciduria type I


Key points

Glutaric aciduria type I (GA1) is an inborn error of metabolism - a mitochondrial disorder resulting in glutaryl-coenzyme A dehydrogenase (GCDH) deficiency. CGDH is involved in the metabolism of lysine and tryptophan.
Patients suffer from encephalopathic crises and experience severe dystonic-dyskinetic movements.
Patients initially develop normally. Most will become severely disabled. 20% die before age 5.
Early treatment can prevent or lessen symptoms.
Common imaging features include widened operculae (frontotemporal atrophy) – so called "bat wing" configuration of the Sylvian fissures. Also common are bright basal galglia and diffuse white matter gliosis.
Can mimic child abuse. Marked cerebral atrophy predisposes these children to bridging vein injuries resulting in subdural hematomas from minor trauma.