Iron stores and cerebral veins in MS studied by susceptibility

Department of Radiology, Wayne State University, Detroit, MI, USA2 Department of Radiology, the First Affiliated Hospital, Dalian Medical University, Dalian, China.
International angiology: a journal of the International Union of Angiology (Impact Factor: 0.83). 04/2010; 29(2):149-57.
Source: PubMed


In this paper, we seek to determine whether the iron deposition as seen by susceptibility weighted imaging (SWI) in the basal ganglia and thalamus of patients with multiple sclerosis is greater than the iron content measured in normal subjects (individuals unaffected by multiple sclerosis). As increased iron content may result from increased venous pressure, such information would add credence to the concept of Zamboni et al (1) that MS is caused by chronic cerebrospinal venous insufficiency.
Fourteen MS patients were recruited for this study with a mean age of 38 years ranging from 19 to 66 year-old. A velocity compensated 3D gradient echo sequence was used to generate SW images with a high sensitivity to iron content. We evaluated iron in the following structures: substantia nigra, red nucleus, globus pallidus, putamen, caudate nucleus, thalamus and pulvinar thalamus. Each structure was broken into two parts, a high iron content region and a low iron content region. The measured values were compared to previously established baseline iron content in these structures as a function of age.
Twelve of fourteen patients had an increase in iron above normal levels and with a particular pattern of iron deposition in the medial venous drainage system that was associated with the confluence of the veins draining that structure.
Iron may serve as a biomarker of venous vascular damage in multiple sclerosis. The backward iron accumulation pattern seen in the basal ganglia and thalamus of most MS patients is consistent with the hypothesis of venous hypertension.

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    • "Iron is a cofactor in CNS myelination; thus, its deficiency may play a role in demyelination [13]. MS has been also associated with the abnormal accumulation of iron in the basal ganglia and thalamus [14]. However CSF iron concentrations are reported to be increased in chronic progressive MS [15]; since in our case RLS is the initial presentation of MS, most probably RLS is caused by the demyelination process in MS as emphasized before [16], not due to axonal degeneration related to iron accumulation. "
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    ABSTRACT: The restless legs syndrome (RLS) is a common central nervous system disorder. It is characterized by complaints of unpleasant sensation in the legs occurring during periods of leg inactivity which worsen or only occur in the evening or at night and relieved partially or totally by movement. The RLS may be idiopathic or due to secondary causes. It is associated with several pathological or physiological conditions. Iron metabolism and dysfunctions of the dopaminergic system are the most important factors in the pathophysiology. There are several studies suggesting multiple sclerosis as one of the causes of symptomatic RLS. Here, we report a case of RLS as the initial presentation of MS. The sudden onset of RLS symptoms in our patient suggested the possibility of an underlying cause. His diagnostic evaluation excluded other causes of RLS and his clinical course suggested that RLS was due to MS. MS with the spinal cord involvement is mostly associated with RLS, but any lesion in the hypothalamic-spinal connection may cause disinhibition of lower spinal levels, resulting in RLS. RLS as the initial presentation of MS reflects that the pathophysiology of RLS in MS is related to inflammatory demyelination rather than axonal degeneration.
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    • "First described by Zamboni and co-workers, CCSVI is characterized by impaired extracranial venous drainage, notably in the internal jugular veins (IJVs), vertebral veins (VVs), and deep cerebral veins (DCVs), and the formation of collateral vessels [6]. It has been proposed that CCSVI may lead to increased iron deposition in the brain, leading to an inflammatory or immune reaction and the formation of MS lesions [5], [6], [9], [10], [11]. Percutaneous transluminal angioplasty and stenting have emerged as potential treatment options for MS patients as a result of this new hypothesis [12]. "
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    ABSTRACT: An alternative hypothesis has been proposed implicating chronic cerebrospinal venous insufficiency (CCSVI) as a potential cause of multiple sclerosis (MS). We aimed to evaluate the validity of this hypothesis in a controlled animal model. Animal experiments were approved by the institutional animal care committee. The jugular veins in SJL mice were ligated bilaterally (n = 20), and the mice were observed for up to six months after ligation. Sham-operated mice (n = 15) and mice induced with experimental autoimmune encephalomyelitis (n = 8) were used as negative and positive controls, respectively. The animals were evaluated using CT venography and (99m)Tc-exametazime to assess for structural and hemodynamic changes. Imaging was performed to evaluate for signs of blood-brain barrier (BBB) breakdown and neuroinflammation. Flow cytometry and histopathology were performed to assess inflammatory cell populations and demyelination. There were both structural changes (stenosis, collaterals) in the jugular venous drainage and hemodynamic disturbances in the brain on Tc99m-exametazime scintigraphy (p = 0.024). In the JVL mice, gadolinium MRI and immunofluorescence imaging for barrier molecules did not reveal evidence of BBB breakdown (p = 0.58). Myeloperoxidase, matrix metalloproteinase, and protease molecular imaging did not reveal signs of increased neuroinflammation (all p>0.05). Flow cytometry and histopathology also did not reveal increase in inflammatory cell infiltration or population shifts. No evidence of demyelination was found, and the mice remained without clinical signs. Despite the structural and hemodynamic changes, we did not identify changes in the BBB permeability, neuroinflammation, demyelination, or clinical signs in the JVL group compared to the sham group. Therefore, our murine model does not support CCSVI as a cause of demyelinating diseases such as multiple sclerosis.
    Full-text · Article · Mar 2012 · PLoS ONE
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    • "Adams (1988) found that the iron deposition in MS reflected damage to vessel walls and " old " hemorrhages in the vicinity of plaques, and that the incidence of hemosiderin deposition in MS was 30% compared to 6% in non-MS cases; furthermore, he suggested that inflammation in vessel walls might be exacerbated by surges in intracranial venous pressure. Haacke et al. (2010) found that increased iron content in MS basal ganglia and thalamus formed a particular pattern of iron deposition in the medial venous drainage system at the confluence of the veins draining these structures . Zamboni (2006) postulated that iron mobilised from such deposits may enter the brain parenchyma and become the source of damage to neurons, thereby promoting disability progression. "
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    ABSTRACT: Although the involvement of immune mechanisms in multiple sclerosis (MS) is undisputed, some argue that there is insufficient evidence to support the hypothesis that MS is an autoimmune disease, and that the difference between immune- and autoimmune disease mechanisms has yet to be clearly delineated. Uncertainties surrounding MS disease pathogenesis and the modest efficacy of currently used disease modifying treatments (DMTs) in the prevention of disability, warrant the need to explore other possibilities. It is evident from the literature that people diagnosed with MS differ widely in symptoms and clinical outcome--some patients have a benign disease course over many years without requiring any DMTs. Attempting to include all patients into a single entity is an oversimplification and may obscure important observations with therapeutic consequences. In this review we advocate an individualised approach named Pathology Supported Genetic Testing (PSGT), in which genetic tests are combined with biochemical measurements in order to identify subgroups of patients requiring different treatments. Iron dysregulation in MS is used as an example of how this approach may benefit patients. The theory that iron deposition in the brain contributes to MS pathogenesis has caused uncertainty among patients as to whether they should avoid iron. However, the fact that a subgroup of people diagnosed with MS show clinical improvement when they are on iron supplementation emphasises the importance of individualised therapy, based on genetic and biochemical determinations.
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