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.
Studies reporting prevalance 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.
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.
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, predonimantly 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, recently 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 changes are usually only notable on MRI, with CT often being unremarkable.
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 effected 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.
Treatment and prognosis
Management varies considerably, depending on whether the hemochromatosis is primary or secondary, and what clinical manifestations are present 5,6.
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- 2. Kontogeorgos G, Handy S, Kovacs K, Horvath E, Scheithauer BW. The Anterior Pituitary in Hemochromatosis. (1996) Endocrine pathology. 7 (2): 159-164. Pubmed
- 3. Kumar N, Rizek P, Sadikovic B, Adams PC, Jog M. Movement Disorders Associated With Hemochromatosis. (2016) The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. 43 (6): 801-808. doi:10.1017/cjn.2016.286 - Pubmed
- 4. Nielsen JE, Jensen LN, Krabbe K. Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome. (1995) Journal of neurology, neurosurgery, and psychiatry. 59 (3): 318-21. Pubmed
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- 7. Schenck JF. Magnetic resonance imaging of brain iron. (2003) Journal of the neurological sciences. 207 (1-2): 99-102. Pubmed
- 8. Dusek P, Jankovic J, Le W. Iron dysregulation in movement disorders. (2012) Neurobiology of disease. 46 (1): 1-18. doi:10.1016/j.nbd.2011.12.054 - Pubmed
- 9. Sadrzadeh SM, Saffari Y. Iron and brain disorders. (2004) American journal of clinical pathology. 121 Suppl: S64-70. Pubmed
- 10. Fujisawa I, Morikawa M, Nakano Y, Konishi J. Hemochromatosis of the pituitary gland: MR imaging. (1988) Radiology. 168 (1): 213-4. doi:10.1148/radiology.168.1.3380960 - Pubmed
- 11. Stankiewicz J, Panter SS, Neema M, Arora A, Batt CE, Bakshi R. Iron in chronic brain disorders: Imaging and neurotherapeutic implications. (2007) Neurotherapeutics. 4 (3): 371. doi:10.1016/j.nurt.2007.05.006 - Pubmed
- 12. Kira R, Ohga S, Takada H, Gondo K, Mihara F, Hara T. MR choroid plexus sign of iron overload. (2000) Neurology. 55 (9): 1340. Pubmed