Neuroimaging in Friedreich’s ataxia

Neuroimaging can play a role in Friedreich’s ataxia (FA) diagnosis when the presentation is atypical.

Brain and occasionally spinal cord MRI is the standard modality, although tissue loss may not be apparent on such scans until later in the course of the slowly progressive disease. Thus, they are only useful for ruling out other conditions or identifying non-FA complicating factors.

Imaging hallmarks of FA

For research studies, neuroimaging can be a useful tool. Still, brain and spinal cord MRIs are usually normal at the time of an FA diagnosis. Volumetric data can suggest spinal cord atrophy, but this may be difficult to detect in clinical scans.

Eventually, the following structural changes are observed in the typical course of FA:

• thinning of the cervical spinal cord
• mild or moderate cerebellar atrophy
• mild cerebral atrophy

Diffusion weighted imaging can reveal microstructural alterations in the brain and spinal cord. Neuroimaging abnormalities in FA progressively become more apparent over time, correlating with clinical disability in affected individuals. However, such correlations are modest and observed in population data rather than single patients, making their clinical usefulness low.

Spinal cord

MRI evaluations can show flattening and reduced cross-sectional area of the spinal cord, most markedly in cervical regions, reflecting involvement of the dorsal columns and corticospinal tract.

This spinal cord pathology is among the earliest changes that can be observed in FA neuroimaging. But its absence means little, and such changes are mainly useful in research situations.

Hypoplasia of the cervical spinal cord in childhood followed by ongoing neurodegeneration contributes to a growing difference in spinal cord area between individuals with or without FA over time in research studies.

Diffusion weighted imaging may show lower fractional anisotropy and higher diffusivity suggestive of microstructural alterations in the FA spinal cord. A decreased tNAA/mIns ratio on magnetic resonance spectroscopy may show evidence of neurodegenerative processes before overt tissue loss is observed. But these are, again, useful almost solely in research studies.

Cerebellum

A pattern of atrophy in the cerebellum is observed, particularly in lobules IV-VI of the vermis. Reductions in brainstem and cerebellar white matter volume adjacent to the dentate nuclei and within the cerebellar peduncles have been described.

Reduced superior cerebellar peduncle volume is already evident in childhood and becomes more pronounced with age. Microstructural alterations in the cerebellar peduncles have also been described. These changes are seen best in high-strength magnet MRI scans under research protocols and are not useful for patient management.

Quantitative susceptibility mapping shows atrophy of the dentate nuclei alongside increased iron accumulation. This is again useful purely on a research basis.

Due to cerebellar and brainstem atrophy, the fourth ventricle may appear enlarged for the individual with FA.

Cerebellar atrophy in FA is generally not as severe as that observed in other spinocerebellar ataxias.

Cerebrum

Cerebral atrophy may not be evident in children with FA, but mild atrophy may be observed in later disease stages, particularly in the thalamus and cortical motor areas, due to advanced neurodegeneration.

Microstructural white matter abnormalities can be detected in corticospinal, callosal, and long-range association tracts.

Cerebro-cerebellar functional connectivity as assessed via functional MRI may also be altered. Again, all of the data on cerebral imaging is useful essentially only in a research context.

Ruling out differential diagnoses

Careful analysis of neuroimaging data can exclude other diagnoses, although genetic testing is the definitive way to diagnose FA and, in many situations ,imaging may not truly be required.

MRI imaging may identify acquired or structural causes of ataxia such as intracranial neoplasms, congenital malformations, infections, or stroke. However, these usually create clinical features that are atypical for FA (headache, lateralizing features, rapid progression or apoplectic onset, sparing of reflexes, and atypical age or ethnic background for FA).

There may be overlap with other forms of inherited ataxias, such as spinocerebellar ataxias, but such disorders usually exhibit more significant cerebellar atrophy than that seen with FA.

Serial MRI scans are insensitive to change compared with patient features (complaints, exam findings) and thus have essentially no value in clinical monitoring.