anemia major cause of movement disorder a treatable and curable neurological syndrome if early detected see what happens if late

1. A CASE OF RESTLESS
LEGS SYNDROME
M4 CLUB
15-11-11

2. CASE HISTORY
Saritha 15 Yrs F
STUDENT
Kottarakara
Trivandrum

3. C/O
 Easy fatiguability
 Dyspnoea on exertion
 Palpitation
 Poor concentration in studies
6 months
 Anger, irritability, restlessness
 Decreased sleep
 Unpleasant sensations in calf
 Urge to move her lower limbs

4. Continued-
 All these were progressing slowly
 finally disabling her to attend school
 H/o pica for raw rice &non edible
substances
 H/o decreased food intake
 No H/o menorrhagia

5. History
 No Menorrhagia / Amenorrhoea
 No Hypertension, Diabetes, Heart
disease
 No Joint pain, Kidney disease
 No H/o hospitalisation

6. Family History

7. Personal history
 Attained menarche -12 yrs
 Normal menstrual cycles
 Constipated
 Bladder habits normal
 No addictions/ habituations

8. O/E
 Moderately built & Poorly nourished
 BMI- 22
 Pallor ++
 Severe Glossitis ++
 Koilonychia +
 Pulse - 74/mt
 BP 94/70 mm of Hg
 RR- 14/mt
 Temperature- Normal

9. System exam
NS –
HMF- NAD
Cranial Nerves- NAD
Motor system- NAD
Sensory system- NAD
 ADHD?
 Restless legs
 Akathisia?

11.  No Hepato splenomegaly
 CVS - No cardiomegaly
 RS - WNL
 GUS-N

12. Differential Diagnosis
– to Differentiate from RLS
 Peripheral Neuropathy
No circadian changes
No periodic leg movements in sleep
Nerve conduction abnormal
No improvement with movement
 Akathisia
No circadian pattern
No paresthesia
Improvement from dopamine blockers

13. DD
 Peripheral Vascular Disease
Worse with movement, better with rest
Vascular and skin changes seen on exam
 Nocturnal Leg Cramps
Unilateral, focal, sudden severe onset
 Painful Legs and Moving Toes
No urge to move, no worsening at rest or
improvement with movement
No circadian changes

14. Inv
 Hb- 3.8gm%
 TC- 5440
 ESR- 32
 Pl ct - 3.1 lac
 MCV- 53.2
 MCH- 12
 MCHC- 22.6
 Ret ct – 1.4 %
 Stool R/E No ova/ parasites

15. Peri smear-
Microcytic Hypochromic anemia
S/o iron deficiency anemia

16. INV
S Ferritin- 3 ng/ml
Stool occult blood – positive
Blood urea- 25
S Creatinine – 0.8
RBS - 97
OT/PT- 38/18
Thyroid functions- N

17. 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.

18. FINAL DIAGNOSIS
 Restless Legs Syndrome
 Iron deficiency Anemia
 Hypoferritinemia
 Family history of anemia, Familial?

19. 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
one's body to stop uncomfortable or
odd sensations, particularly during rest
relieved by voluntary or involuntary
movement.

20. 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.

21. Role of Iron
Iron is necessary for the production of tyrosine
hydroxylase
The rate-limiting step in the production of
levodopa
which is then decarboxylated to dopamine

23. 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.

24. Substantia nigra
The substantia nigra, a “movement center”
of the brain and the focal area of
pathology in RLS
Do not have the capacity to store iron as
ferritin
But instead rely on a weaker iron-
containing pigment known as
neuromelanin.

25. Ferrous iron -toxic hydroxyl
radicals in neuronal tissue
Movement 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.

27. Low CSF Iron
Even when levels of serum iron, serum
ferritin, or serum transferrin are not lower
than normals
CSF levels of storage iron have been shown to
be significantly lower in RLS
CSF ferritin was 65% lower and CSF
transferrin was 300% higher in patients with
RLS compared to age-matched controls.

28. MRI- Brain biopsies - RLS
MRI measurements of brain iron,
Transcranial sonography &
Brain biopsies
showed significantly less iron in the
substantia nigra compared to
controls, with decreased levels
proportionate to the severity of RLS
symptoms.

29. H-ferritin staining in the SN after bleaching of neuromelanin
The 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 the
immunoreactionproduct for H-ferritin.

30. Night time low ferritin in CSF- early
onset RLS- before age 45
Although 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.

31. Lowest iron levels -maximal severity of RLS
The 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).

32. Iron is trafficked to the mitochondria
by 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

33. 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

34. 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

35. 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 .

36. 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.

37. Quantification of mitochondrial ferritin (FtMt) in the SN.
FtMt levels are significantly increased (51%) in RLS compared to
control autopsy SN homogenates (p < 0.01).

38. Mitochondrial ferritin (FtMt) immunostaining in the substantia nigra (SN).
There is less neuronal FtMt staining in control SN (A) compared to restless leg syndrome
SN. Neuromelanin has been bleached from the neurons; the blue background and
immunoreactionproduct for FtMt are due to the use of nickel chloride in the chromogen
reaction (B). Original

39. Studies of RLS and iron metabolism
have 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.

40. 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.

41. 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.

42.  RLS
 A ferritin related neuropathy?

43. 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

44. CNS- ID/Familial Disorder
RLS 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

45. Nutritional supplementation
Dopamine-agonist medications DAM
Standard laboratory measures may not be
sensitive enough to diagnose iron or folate
insufficiency in the CNS.
Nevertheless, the healthcare provider may
need 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

46. 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.