Table 1.

Radiographic differential diagnosis of Leigh syndrome brain lesions.

Leigh and Leigh-like syndrome
Mutations in >80 disease genes related to mitochondrial energy metabolism (e.g.,	T2 hyperintense bilaterally symmetric brainstem nuclei or basal ganglia lesions; lesions are frequently also found in the cerebellum and spinal cord.	[1]
PDH, OXPHOS)
Genetic defects in thiamine transport/ processing (SLC19A3 and TPK1)	T2 hyperintensities of bilateral basal ganglia, deep gray nuclei; SLC19A3- related disease also involves cortical and subcortical white matter	[54,56]
Organic acidurias, GM1 and GM2 gangliosidoses, guanidinoacetate methyltransferase deficiency	May at times present with T2 hyperintense bilaterally symmetric brainstem nuclei or basal ganglia lesions, often in addition to more canonical white matter or other intracranial disease	[26–28]
Acquired neurologic insult
Hypoxic ischemic injury (HII)	MRI may present with T2 hyperintense lesions of the bilateral putamina and thalami ± bilateral globi pallidi lesions and white matter lesions. HII after the neonatal period tends to spare the thalami.	[12,23]
Hypoglycemic ischemic encephalopathy	Classically involves the occipital cortex in addition to basal ganglia, thalami. T2 lesions preceded by diffusion restriction may evolve into encephalomalacia.	[29]
Refractory status epilepticus	Typically involves pulvinar (+/- cortex), accompanied by diffusion restriction, histopathology similar to Wernicke-Korsakoff lesions.	[30]
Toxic/metabolic
Wernicke-Korsakoff Syndrome (thiamine deficiency)	Uniformly involves mammillary bodies in addition to structures affected in LS; basal ganglia involvement is rare in classical (alcohol use disorder- associated) disease but can occur in pediatric and nonalcohol use disorder- associated adult cases; histology differs from LS in that petechial hemorrhage is often observed.	[31]
Kernicterus (CNS bilirubin toxicity)	T2 hyperintense basal ganglia lesions have been reported as late as 1 year; some reports involve T1 hyperintense lesions.	[32]
Osmotic myelinolysis	Most commonly occurs in individuals with comorbid alcohol use disorder, cases with thalamic and striatal T2 signal changes have been reported.	[33]
Carbon monoxide poisoning	Bilateral globi pallidi are uniformly T2 hyperintense; cerebral cortex, cerebral white matter, cerebellum, midbrain may also be involved. In rare cases, T2 and T1 hyperintensity of the globi pallidi have been observed. Lesions may regress with time.	[34]
Metronidazole encephalopathy	Lesions mostly commonly occur in the brainstem and/or cerebellar dentate nuclei, although basal ganglia are rarely involved. Metronidazole encephalopathy is more common in individuals with comorbid alcohol use disorder.	[35]
Fedratinib toxicity	Reported as rare side effect in individuals being treated for myeloproliferative disorders. T2 hyperintense lesions were observed in the bilateral caudate nuclei, lenticular nuclei, and thalami but not in the mammillary bodies. Clinical and radiographic improvements were reported after thiamine supplementation.	[13]
Disulfiram toxicity	Bilateral globi pallidi and putamina are affected. Most occurrences in individuals with alcohol use disorder being treated with disulfiram; however, one case reported in a child after accidental ingestion.	[14]
Carbon disulfide toxicity	This industrial solvent is metabolized by cytochrome P450 enzymes to thiocarbamide, 2-mercapto-2-thiazolinone-5, and 2-thiothiazolidine-4- carboxylic acid, the latter of which conjugates to glutathione. Chronic exposure leads to encephalopathy, parkinsonism, and neuropathy. Imaging features may be suggestive of a microangiopathy.	[15]
Vigabatrin exposure	Lesions occur in ~30% of patients with epilepsy treated with vigabatrin (a GABA transaminase inhibitor) and are diffusion restricting as well as T2 hyperintense. Lesions resolve with discontinuation of therapy.	[16]
Infection-related
Hemolytic-uremic syndrome (HUS)	Lesions often involve splenium of the corpus callosum in addition to structures typically affected in LS, were diffusion-restricting and T2 hyperintense, and resolve in most cases. Edema, necrosis, spongiosis, gliosis, hemorrhages, and thrombotic microangiopathy have all been reported on histology.	[17]
Flavivirus (West Nile, Murray Valley Encephalitis)	Lesions occur in a significant proportion of patients and may be diffusion restricting and T2 hyperintense or diffusion restricting (and resolving) only, with the latter seeming to confer a better prognosis.	[18]
Variant Creutzfeldt-Jakob disease (bovine spongiform encephalopathy)	Pulvinar most commonly affected, dorsomedial thalamic nuclei, caudate head, and periaqueductal gray matter may also be involved. Lesions may regress. Histology is characterized by spongiform change, neuronal loss, astrocytosis, and deposition of partially protease-resistant prion protein.	[19]
Influenza A, B associated encephalopathy/Reye syndrome	Involvement of the splenium of the corpus callosum is often reported in addition to the gray matter structures affected by LS.	[20]
Cerebral malaria	Lesions of gray and white matter have been reported with some authors interpreting the gray matter lesions as resulting from vasogenic edema.	[21]
Other genetic disorders
Wilson disease (ATP7B)	The MRI brain may be normal, but the most common abnormality is a T2 hyperintense signal in the lateral rim of the bilateral putamina. T2 hyperintensity of the caudate, globi pallidi, and thalami were seen only when putaminal lesions were absent. Rarely, T1 hyperintensity may be seen in the thalami. Response of brain lesions to copper chelation remains unclear.	[22]
Menkes disease (ATP7A)	T2 hyperintense lesions of the caudate nuclei, lenticular nuclei, and globi pallidi have been reported. Isolated T2 hyperintensities of the parieto-occipital white matter and isolated cerebral atrophy have also been reported.	[24]
Juvenile Huntington disease (HTT)	Caudate atrophy, similar to adult patients, was observed in addition to T2 signal abnormalities of the caudate, which is not a feature of adult-onset disease. Interestingly, juvenile onset HD mostly typically presents with Parkinsonism, although adult-onset disease is characterized by chorea.	[25]
Dentatorubral-pallidoluysian atrophy (ATN1)	T2 hyperintensity of the globi pallidi and thalami are present with atrophy of the tegmentum, other deep gray nuclei, and cerebellum. Histopathology demonstrates characteristic neuronal intranuclear inclusions.	[26]

MRI, magnetic resonance imaging; OXPHOS, oxidative phosphorylation; GABA, Gamma-Aminobutyric Acid; HD, Huntington Disease; CNS, central nervous system.