Comparison with February 15, 2006.
There is a septation within the frontal horn of the left lateral ventricle which appears unchanged compared with previous from February 15, 2006. The left lateral ventricle is mildly larger than the right, also unchanged from previous. Third ventricle and fourth ventricle are normal in size. There is T2 prolongation with increased signal intensity on the T2 imaging most marked within the region of the olivary nuclei within the medulla, within the periaquaductal gray matter, with minimal increased signal intensity within the dorsomedial medulla. Very minimal T2 prolongation is seen posteriorly within the putamen. The increased signal intensity within the periaqueductal region is less marked than on the previous, however, the increased signal within the lentiform nuclei appear unchanged from previous.No obvious decreased signal intensity is seen on the T1 weighted images within the corresponding areas which are increased in signal on the T2 series. Unfortunately, the images through the medulla on the post-contrast T1 series are compromised by motion artifact from the sigmoid sinus. There is however, no obvious enhancement seen within the region of the olivary nuclei on the axial, coronal or sagittal post-gadolinium series. No obvious evidence for delayed myelination or diffuse demyelination is seen. No MR spectroscopy was performed.

The gray white matter differentiation is normal. No obvious increased signal intensity is seen within the coronal radiata or centrum semiovale or the corpus callosum. Mild thining of the body of the corpus callosum. The pituitary gland, and cerebellar vermis are normal. No cerebellar tonsillar herniation is seen.

The diffusion-weighted series shows increased signal intensity within the region of the olivary nuclei of the medulla bilaterally and very subtle increased signal intensity within the putamen posteriorly on both sides. There is, however, no corresponding decrease signal intensity on the ADC series and this is thus, consistent with T2 or T-shrine through and does not represent changes of acute ischemia. No areas of territorial infarction are seen. No obvious masses, calcifications, mass effect or midline shift is seen. Pars intermedia cyst of the pituitary which appears unchanged compared with previous.

There is bilateral chronic sinusitis with increased signal intensity seen on the T2 series within the maxillary antra, right greater than left which is almost hyperintense with muscle on the T1 weighted series. This is thought to most likely represent inspissated mucous. Polyps cannot be excluded within the right maxillary antrum. The sphenoid sinuses, ethmoid sinus, frontal sinus and the mastoid air cells are normal.


IMPRESSION:
1. The findings are consistent with those of a mitochondrial disorder, most likely secondary to Leigh disease (subacute necrotizing encephalomyelopathy. Other mitochondrial disorders should also be considered in the differential diagnosis. Other considerations in the differential diagnosis include organic aminoacidopathies, but these usually thes have more marked white matter involvement. Toxic ingestions which present with more acute findings, and thiamine deficiency in malnourished children.
2. The major area of involvement is within the medulla in the region of the olivary nuclei which is known to be preferentially affected in infants with Leigh's disease compared with the involvement of the globus pallidi, thalami, and subthalamic nuclei which are more commonly affected in young
children.
3. Pars intermedia cyst of the pituitary which appears unchanged compared with previous.
4. Stable septations within the left frontal horn.
5.The left maxillary mucous retention cyst appears smaller than previous, however, the more marked findings of chronic sinusitis within the right maxillary antrum have developed since the previous exam.

Laboratory investigations have included a blood lactate which was elevated, pyruvate, total and free carnitine and acylcarnitine profile. Genetic testing for identified point mutations that have been associated with mitochondrial disorders and a urine for organic acids were also requested.Previous investigations have included a CSF lactate which was elevated and a muscle biopsy. The muscle biopsy apparently has shown abnormal mitochondria. No definite ragged red fibers were demonstrated.The biopsy specimen has been sent out for a second opinion.

Leigh's disease is one of the mitochondrial cytopathies secondary to disorders of mitochondrial function that result in impaired production of adenosine triphosphate in affected cells. As a result, there is impaired aerobic metabolism of pyruvate which results in anaerobic conversion to lactate and transamination to alanine. Leigh's disease typically affects infants and young children, but there may be later presentations in older children and adults. Genetic and biochemical abnormalities seen in these patients usually include pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency and cytochrome-oxidase deficiency.
The patients present with hypotonia, brainstem dysfunction, ophthalmoplegia, ataxia and ptosis. The clinical course may be acute, relapsing/remitting or slowly progressive. Elevated lactate may be present in the bladder and CSF. MRI spectroscopy is often abnormal showing an elevated lactate peak. There is no specific treatment except for minimizing stresses and infections that may precipitate a metabolic crisis. The disease usually has relentless progressive at a variable right.
Leigh's disease (subacute necrotizing encephalomyelopathy)(Ref 3)
BACKGROUND AND CLINICAL INFORMATION:
General features: Leigh's disease is a subacute necrotizing encephalomyelopathy affecting the gray matter. Histologic features include necrosis, proliferation of blood vessels, gliosis, and preservation of neurons (similar to that of Wernicke’s encephalopathy).
Etiology: the metabolic defects in Leigh's disease is heterogenous but that each causes an impairment in mitochondrial function and hence a chronic energy deprivation syndrome.
Enzymatic defect:
• The most common enzyme defects involve the pyruvate dehydrogenase complex and cytochrome C oxidase. A point mutation at position 8993 of mitochondrial DNA is a common cause. Another mutation is an A to C transversion in the pyruvate dehydrogenase complex E1 alpha-subunit gene (X-linked mutation).
• Mutation at position 3243 has also been reported.
Clinical: Most frequently presented in the first two years of life but rare late onset and adult onset cases are recognized. Clinically, it is characterized by psychomoter retardation, feeding difficulties, hypotonia or weakness and ataxia. Disorders of movent such as dystonias, tremor, chorea and even myoclonus are frequent clinical findngs. Disturbance of respiration and abnormal eye movements with or without optic atrophy are common. It may be difficult to distinguish Leigh's disease from other enzymatic deficiencies that are associated with lactic acidosis. Death occurs within a few years (usually within one year) after the onset of symptoms. Prolonged survival and acute fulminating illness of a few days are both reported before.
• Neonatal presentation: A typical presentation occurs in the neonatal period with hypotonia and recurrent vomiting. Later visual and hearing loss occurs and seizures develop. In some cases, the onset of Leigh disease may be delayed until walking begins. In these patients, ataxia and loss of intellectual development accompanies muscle weakness.
• CSF: lactate and pyruvate concentrations are frequently increased in blood and CSF.
Heredity: About half of the cases show autosomal inheritance. The other half of the cases show X-linked mutations of the E1 subunit of pyruvate dehydrogenase complex, maternal mitochondrial DNA point mutations, or sporadic inheritance of mitochondria DNA deletions.
Clinical progression: Compare to other mitochondrial encephalopathy such as KSS, MELAS, MERRF, Leigh's disease progress much more rapidly and are seen in younger child.
NEUROIMAGING: Head
High-metabolic region of the brain, particularly the putamen, are most commonly involved. MRI demonstrates characteristic symmetrical putamen long-TR hyperintense changes that are also commonly found in the globus pallidus and caudate nucleus.
GROSS PATHOLOGY: Head
General characteristics: Leigh's disease affects mainly the deep gray matter. Lesions are uncommon in the white matter and cerebral cortex. Polymicrogyria may be seen.
The spinal cord, optic nerve and peripheral nerve must be examined.
Characteristically, there are symmetrical lesion in the brain stem and the diencephalon with frequent involvement of the globus pallidus, spinal cord, optic nerve and cerebellum. The pons and medulla are affected in over 98% of cases. In adult cases, the globus pallidus seems to be more affected.
• The lesions are gray brown in color. The individual lesions do not respect the boundries of gray and white matter. Cystic changes can be seen in older cases.
• The most commonly affected structures (>75% of cases) are substantia (95%), inferior (but not superior) colliculus, medullary tegmentum, and spinal gray matter.
HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY:
The topology of microscopic features are very similar to those seen in Wernicke-Korsakoff syndrome. Acute lesions characteristically show a loosening or spongiosus of the neuropil followed by necrosis of tissue. There is a proliferation of capillaries, reactive gliosis and infiltration by macrophages. Perivascular cuffing is occasionally seen. Neurons are relatively preserved even in the center of necrotizing lesions. In contrast to Wernicke-Korsakoff syndrome, the mammillary bodies are rarely affected.
Regional pathology: Changes are most frequently seen in the brain stem, especially the substantia nigra (95% of cases), inferior colliculus, medullary tegmentum, and spinal gray matter.
Torpedo: Cerebellar degeneration is quite common and "torpedo" formation may be seen.
Muscle biopsy: ragged-red fibers can be seen in a few cases.
Ultrastructural changes include numerous vacuoles that appear to be formed by splitting of the myelin.
DIFFERENTIAL DIAGNOSIS: Head
Methyl alcohol intoxication may have multifocal petechial hemorrhage with edema. There may also be necrosis of the putamen with cystic changes suggestive of Leigh’s disease. Methanol is oxidized to formaldehyde and further to formic acid. The possible mechanism is that formic acid inhibits cytochrome C oxidase and impairs functioning of mitochondria.
The differentiation of Leigh's versus Wernicke-Korsakoff syndrome includes:
Leigh's usually occurs during the first two years of life, neonatal
and adult onset cases can be seen. Wernicke's is seen in adults. Both can affect the gray matter. Leigh's disease is due to Mitochondrial dysfunction whereas Wernickes is due to Thiamine deficiency.

References:
1. Anne Osborn, Susan Blaser etal. Diagnostic imaging.Brain. Amirsys. Salt Lake City, Utah. 2004
2. Mauricio Castillo and Suresh Mukherji. Imaging of the head neck and spine. Lipincott-Raven. 1996.
3. http://moon.ouhsc.edu/kfung/jty1/neurohelp/ZNF1IE02.htm
NeuroLearn NeuroHelp Metabolic For Comment: KarMing-Fung@ouhsc.edu
Background Neuroimaging Gross Pathology Histopathology & Immunohistochemistry Differential Diagnosis

Case Number: 5072971Last Updated: 06-27-2006
Anatomy: Cranium and Contents   Pathology: Metabolic
Modality: MR, PathologyExam Date: Access Level: Readable by all users
Keywords: suspected mitochondrial disorder. probably leigh's disease (subacute necrotizing encephalomyelopathy)

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