No Hepato splenomegaly CVS - No cardiomegaly RS - WNL GUS-N
Differential Diagnosis– to Differentiate from RLS Peripheral NeuropathyNo circadian changesNo periodic leg movements in sleepNerve conduction abnormalNo improvement with movement AkathisiaNo circadian patternNo paresthesiaImprovement from dopamine blockers
DD Peripheral Vascular DiseaseWorse with movement, better with restVascular and skin changes seen on exam Nocturnal Leg CrampsUnilateral, focal, sudden severe onset Painful Legs and Moving ToesNo urge to move, no worsening at rest orimprovement with movementNo circadian changes
NIH criteria, Modified (2003)1. An urge to move the limbs with or without sensations.2. Improvement with activity. Many patients find relief when moving and the relief continues while they are moving. In more severe RLS this relief of symptoms may not be complete or the symptoms may reappear when the movement ceases.3. Worsening at rest. Patients may describe being the most affected when sitting for a long period of time, such as when traveling in a car or airplane, attending a meeting, or watching a performance. An increased level of mental awareness may help reduce these symptoms.4. Worsening in the evening or night. Patients with mild or moderate RLS show a clear circadian rhythm to their symptoms, with an increase in sensory symptoms and restlessness in the evening and into the night.
FINAL DIAGNOSIS Restless Legs Syndrome Iron deficiency Anemia Hypoferritinemia Family history of anemia, Familial?
Discussion Restless legs syndrome (RLS) or Willis- Ekbom disease is a neurological disorder A sensorimotor disorder that may affect 5% to 10% of the population More common in women than in men Characterized by an irresistible urge to move ones body to stop uncomfortable or odd sensations, particularly during rest relieved by voluntary or involuntary movement.
RLS Circadian rhythm to the symptoms, with sensory symptoms Resulting movements increased in the evening and peak at night Etiopathology of RLS may involve iron storage in certain brain centers.
Role of IronIron is necessary for the production of tyrosinehydroxylaseThe rate-limiting step in the production of levodopawhich is then decarboxylated to dopamine
Folate- dopamine-Tetrahydrobiopterin- RLS symptoms Folate is also involved in the production of dopamine in the CNS. Folate, as 5- methyltetrahydrofolate, increases production of CNS tetrahydrobiopterin, a cofactor in tyrosine hydroxylase production . Tetrahydrobiopterin also has a circadian pattern that modulates dopamine production – a daytime increase and an evening nadir. These mechanisms may be responsible for the ability of folate supplementation to reverse RLS symptoms.
Substantia nigraThe substantia nigra, a “movement center” of the brain and the focal area of pathology in RLSDo not have the capacity to store iron as ferritinBut instead rely on a weaker iron- containing pigment known as neuromelanin.
Ferrous iron -toxic hydroxylradicals in neuronal tissueMovement into & out of neuronal cells is tightly regulated by a series of Iron transport mechanisms that allow iron to be exported out of the neuron into brain interstitial cells to prevent iron excess in neuronal tissue.IDA effects the dopamine transports system in pre-synaptic neurons in the striatum, resulting in a net decrease in the reuptake of dopamine and altered neurotransmission.
Low CSF IronEven when levels of serum iron, serum ferritin, or serum transferrin are not lower than normalsCSF levels of storage iron have been shown to be significantly lower in RLSCSF ferritin was 65% lower and CSF transferrin was 300% higher in patients with RLS compared to age-matched controls.
MRI- Brain biopsies - RLSMRI measurements of brain iron,Transcranial sonography &Brain biopsiesshowed significantly less iron in the substantia nigra compared to controls, with decreased levels proportionate to the severity of RLS symptoms.
H-ferritin staining in the SN after bleaching of neuromelaninThe blue reaction product in the neurons in control tissue (A) is more intense than in the RLS)neurons(B).Brown neuromelanincan be detected in the RLS neurons (B) because of the relative absence of theimmunoreactionproduct for H-ferritin.
Night time low ferritin in CSF- earlyonset RLS- before age 45Although ferritin levels in RLS are often “low normal” (i.e., above the lab reference range low of 20 ng/mL), a specific threshold of inadequate iron storage has been identified as the determining factor in these patients.Ferritin concentrations of <50 ng/mL have been correlated with decreased sleep efficiency, increased leg movements in sleep, and increased symptom severity (insomnia and paresthesias)Iron concentrations in the blood have a circadian rhythm, exhibiting a 50- to 60-percent lower serum level at night compared to daytime levels.
Lowest iron levels -maximal severity of RLSThe lowest point in serum iron levels has been found to coincide with the maximal severity of RLS symptoms and is thought to be responsible for the worsening of RLS symptoms in the evening.This diurnal variation of serum iron is also reflected in central nervous system (CNS) iron storage.One study found that nighttime levels of ferritin in cerebrospinal fluid (CSF) were significantly lower in RLS, particularly in early-onset RLS (before age 45).
Iron is trafficked to the mitochondriaby proteins Iron is trafficked to the mitochondria by proteins of the ATP-binding cassette family. Recently it has also been suggested that iron loading into the mitochondria can occur through mitoferrin How iron is subsequently managed is not understood
ROS Inadequately managed iron can lead to oxidative stress reactive oxygen species(ROS), which are produced by mitochondria themselves due to oxidative phosphorylation within the electron transport chain. ROS disrupt mitochondrial function; indeed, a considerable body of the literature has evolved around mitochondrial dysfunction in neurological disorders
SN in autopsy tissue Within the brain, histological examination of the SN in autopsy tissue samples has suggested decreased iron in melanin-containing neurons in RLS compared to controls immunostaining and quantitative analyses have revealed an increase in transferrin and decrease in ferritin and transferrin receptor
Cellular iron deficiency This pattern of expression of transferrin and ferritin indicates cellular iron deficiency Iron has many roles at the cellular level but it is an essential component of many mitochondrial enzymes. It is a required co-factor for enzymes of the respiratory chain in complexes I-IV and can also regulate translation of the 75-kDa subunit of complex I and complex II .
FtMt FtMt levels and mitochondrial numbers are increased in the SN in RLS. The augmentation in mitochondria may reflect cellular attempts to correct metabolic insufficiency in these cells, which in turn may lead to cytosolic iron deficiency.
Quantification of mitochondrial ferritin (FtMt) in the SN.FtMt levels are significantly increased (51%) in RLS compared tocontrol autopsy SN homogenates (p < 0.01).
Mitochondrial ferritin (FtMt) immunostaining in the substantia nigra (SN). There is less neuronal FtMt staining in control SN (A) compared to restless leg syndromeSN. Neuromelanin has been bleached from the neurons; the blue background andimmunoreactionproduct for FtMt are due to the use of nickel chloride in the chromogenreaction (B). Original
Studies of RLS and iron metabolismhave revealed a key role for low brain iron concentrations in altered dopamine levels.An assessment of individuals in all groups with a high incidence of iron deficiency – pregnancy, end-stage renal disease, anemia – found a 25- to 30-percent incidence of RLS.Conversely, in one study 75 percent of individuals with RLS symptoms demonstrated decreased iron stores.Another retrospective study found that, although 62.5 percent of RLS patients had low serum iron and 77 percent had low iron saturation, only 21 percent had red blood cell (RBC) indices of anemia and only 25 percent had low ferritin levels.Significant decline in serum ferritin (32.5 ng/mL in RLS versus 59 ng/mL in controls) has been seen in elderly patients with RLS.
MEIS1 A recent genome wide association study identified an association between RLS and intronic markers from theMEIS1 gene. Comparative genomic analysis indicates that MEIS1 is the only gene encompassed in this evolutionarily conserved chromosomal segment, i.e. a conservation synteny block, from mammals to fish.
lymphoblastoid cell lines (LCLs) Decreased MEIS1 protein levels in the same batch of LCLs and brain tissues from the homozygous carriers of the risk haplotype, compared with the homozygous non-carriers. These data suggest that reduced expression of the MEIS1 gene, possibly through intronic cis-regulatory element(s), predisposes to RLS.
RLS RLS has been closely associated with decreased concentration of iron in the brain and alterations in expression of iron management proteins. Both MRI and Biopsy (SN) of RLS patients . Moreover, cerebrospinal fluid from RLS patients reflects an iron-deficient profile as demonstrated by decreased ferritin and increased transferrin. Indeed, decreased CSF ferritin has been a consistent finding in early onset RLS. In contrast, plasma iron, ferritin, and transferrin levels that reflect systemic iron status are in general within normal ranges in RLS patients
CNS- ID/Familial DisorderRLS is a movement disorder that affects a significant number of individuals with decreased levels of CNS iron or a familial disorder involving CNS dopamine production.The serious sleep disorder associated with RLS necessitates increased awareness among healthcare providers.Groups at risk for iron deficiency – the elderly, pregnant women, and individuals with end-stage renal disease – may need to be universally screened
Nutritional supplementationDopamine-agonist medications DAMStandard laboratory measures may not besensitive enough to diagnose iron or folate insufficiency in the CNS.Nevertheless, the healthcare provider mayneed to address iron or folate supplementation in these patients.DAM carry significant risk of side effects and do not address the underlying etiology of RLS
1. Estimates suggest that over one third of the world’s population suffers from anemia, mostly iron deficiency anemia.2. India continues to be one of the countries with very high prevalence.3. National Family Health Survey (NFHS-3) reveals the prevalence of anemia to be 70-80% in children, 70% in pregnant women and 24% in adult men.4. Prevalence of anemia in India is high because of low dietary intake, poor availability of iron and chronic blood loss due to hook worm infestation and malaria.5. While anemia has well known adverse effects on physical and cognitive performance of individuals, the true toll of iron deficiency anemia lies in the ill-effects on maternal and fetal health.6. Poor nutritional status and anemia in pregnancy have consequences that extend over generations.