Leigh's disease (subacute necrotizing encephalomyelopathy)

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Background    Neuroimaging    Gross Pathology    Histopathology & Immunohistochemistry Differential Diagnosis    

BACKGROUND AND CLINICAL INFORMATION: Head  

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: Head  

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.

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.

Leigh’s disease vs. Wernicke-Korsakoff syndrome

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Background    Neuroimaging    Gross Pathology    Histopathology & Immunohistochemistry Differential Diagnosis