Hemochromatosis (CNS manifestations)

Central nervous system manifestations of hemochromatosis are uncommon and can occur in either primary or secondary hemochromatosis.

For a general discussion, and for links to other system specific manifestations, please refer to the article on hemochromatosis.

Epidemiology

Studies reporting prevalence of CNS involvement in hemochromatosis vary significantly, with rates of symptomatic pituitary gland involvement ranging from 6-100% depending on study size ¹. It is likely that the true prevalence is low ¹.

Clinical presentation

Although CNS involvement in hemochromatosis may be asymptomatic and incidentally noted radiographically, patients may present with:

• hypopituitarism, especially hypogonadotropic hypogonadism ^1,2

• movement disorders (e.g. parkinsonism, Parkinson-plus syndromes, chorea, myoclonus, ataxia, dystonia, or tremor) ^3,4

Patients tend to also exhibit other manifestations of hemochromatosis, such as hepatic, pancreatic, or cardiac dysfunction.

Pathology

Primary hemochromatosis is an autosomal recessive condition due to a defect in the HFE gene, responsible for the HFE protein ^5,6. The HFE protein has a role in interacting with transferrin receptors, to reduce their affinity for transferrin, and also hepcidin, therefore regulating iron transport ^5,6. Secondary hemochromatosis, on the other hand, is associated with chronic blood transfusions or conditions with high erythrogenic requirements (e.g. thalassemia) ⁶.

In hemochromatosis, iron deposition in the brain is uncommon because the blood-brain barrier protects the brain from systemic iron overload, which means that siderosis generally occurs in regions without a blood-brain barrier, such as the choroid plexus and circumventricular organs ^7-9. Additionally, iron deposition also commonly occurs in the anterior pituitary gland, predominantly in gonadotrophs, leading to hypogonadotropic hypogonadism, although reasons for anterior pituitary gland involvement are yet to be fully elucidated ².

In regards to parenchymal siderosis, the HFE protein has been shown to be present in some cerebral blood vessels, potentially leading to parenchymal iron deposition, especially in the basal ganglia, resulting in various movement disorders ^7-9. Furthermore, injury or impairment to the blood-brain barrier, such as impairment which can occur naturally through aging, can also increase the risk of parenchymal siderosis ^7-9.

Radiographic features

Radiographic changes are usually only notable on MRI, with CT often being unremarkable.

MRI

Similar to its effect in other regions of the body, iron causes magnetic susceptibility artefact, which results in characteristic signal changes ^3,10-12:

• T1: variable, both hypointense and hyperintense appearances have been reported

• T2: hypointense

• GRE/SWI: hypointense

The regions classically affected include the choroid plexus (termed the 'MR choroid plexus sign' in one study ¹²), anterior pituitary gland, and circumventricular organs (e.g. pineal gland, area postrema), however deposition within the basal ganglia has also been reported ^3,10,11.

Additionally, patients may have neuroradiological changes associated with complications of hemochromatosis, such as hepatic encephalopathy, which have distinct radiographic features.

Treatment and prognosis

Management varies considerably, depending on whether the hemochromatosis is primary or secondary, and what clinical manifestations are present ^5,6.