Restless legs syndrome as an atypical case of PANDAS? Austin Journal of Clinical Medicine

Abstract

Background: Restless legs syndrome, also known as Willis-Ekbom disease or Wittmaack-Ekbom syndrome, is a neurological disorder characterized by an irresistible urge to move the body to stop uncomfortable or odd sensations. Moving the affected body part modulates the sensations, providing temporary relief. PANDAS is an acronym for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections, a hypothetical subset of conditions in which children are thought to exhibit an extremely abrupt onset of obsessive-compulsive disorder and/or tic disorders symptoms following Group A Beta-Hemolytic Streptococcal (GABHS) infections, with a relapsing-remitting (not waxing-waning) course. Our data highlight the close clinical similarity between Restless Legs Syndrome and PANDAS; in our opinion these two disorders may be distinguishable using laboratory test with the aim of identifying the etiologic agents of PANDAS. This case report presentation could be useful for the pediatrician that may chance upon a similar case.

Full text

Citation: Tromba V, Spalice A, Lambiase C, Favoriti A and Tancredi G. Restless Legs Syndrome as an Atypical
Case of PANDAS?. Austin J Clin Med. 2017; 4(1): 1030.
Austin J Clin Med - Volume 4 Issue 1 - 2017
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Austin Journal of Clinical Medicine
Open Access
Abstract
Background: Restless legs syndrome, also known as Willis-Ekbom disease
or Wittmaack-Ekbom syndrome, is a neurological disorder characterized by an
irresistible urge to move the body to stop uncomfortable or odd sensations.
Moving the affected body part modulates the sensations, providing temporary
relief. PANDAS is an acronym for Pediatric Autoimmune Neuropsychiatric
Disorders Associated with Streptococcal infections, a hypothetical subset of
conditions in which children are thought to exhibit an extremely abrupt onset of
obsessive-compulsive disorder and/or tic disorders symptoms following Group
A Beta-Hemolytic Streptococcal (GABHS) infections, with a relapsing-remitting
(not waxing-waning) course. Our data highlight the close clinical similarity
between Restless Legs Syndrome and PANDAS; in our opinion these two
disorders may be distinguishable using laboratory test with the aim of identifying
the etiologic agents of PANDAS. This case report presentation could be useful
for the pediatrician that may chance upon a similar case.
Case Presentation: Our objective is to describe clinical features of an
atypical presentation of PANDAS in an Italian boy presenting restless leg
syndrome. A 7 year-old boy that suffered for about one year from intense itching,
forcing him to make continuous movements and stereotyped patterns of rotation
of the limbs in order to nd relief. The patient undergone in another hospital
routine and specic laboratory data, including anti-streptolysin O titer. In addition
he was investigated with neurologic and cardiologic assessment with EEG,
SEP, MEP, polysomnography and medullary MRI, cardiologic examination, ECG
and echocardiography: these were all normal. Blood tests showed only mild
hypereosinophilia, elevated Antistreptolysin O antibody titers (ASO 329IU/ml)
and low iron levels. He was discharged with the diagnosis of “Restless Legs
Syndrome” (RLS) and began therapy with gabapentin 100mg twice daily and
iron, without benet. Suspecting movement disorders associated with GABHS
infection, we started, after previous ineffective therapy, administration of benzyl
penicillin every 20 days, until the next follow-up. After three months of follow-up
the boy’s disorders had disappeared and the ASO titer was stable. The boy was
in good clinical condition and no other movement disorders had appeared.
Conclusions: Our data conrm that patients with suspected restless leg
syndrome could present PANDAS.
Keywords: Group-A beta hemolytic streptococcal infection; PANDAS;
Obsessive-compulsive symptoms; Autoimmunity; Restless legs syndrome
Background
Restless Legs Syndrome (RLS), also known as Willis-Ekbom
Disease (WED) or Wittmaack-Ekbom syndrome is a neurological
disorder characterized by an irresistible urge to move the body to
stop uncomfortable or odd sensations. It most commonly aects the
legs, but can aect the arms, torso, head, and even phantom limbs.
Moving the aected body part modulates the sensations, providing
temporary relief.
RLS sensations range from pain or an aching in the muscles, to
“an itch you can’t scratch”, an unpleasant “tickle that won’t stop”, or
even a “crawling” feeling. e sensations typically begin or intensify
during quiet wakefulness, such as when relaxing, reading, studying,
or trying to sleep. Additionally, most individuals with RLS suer from
Special Article - Clinical Case Reports
Restless Legs Syndrome as an Atypical Case of PANDAS?
Tromba V1*, Spalice A2, Lambiase C1, Favoriti A1
and Tancredi G1
1Childhood Cardiology Division, Department of Pediatrics
and Childhood Neuropsychiatry, Sapienza University of
Rome, Rome, Italy
2Childhood Neurology Division, Department of Pediatrics
and Childhood Neuropsychiatry, Sapienza University of
Rome, Rome, Italy
*Corresponding author: Valeria Tromba, Childhood
Cardiology Division, Department of Pediatrics and
Childhood Neuropsychiatry, Umberto I Hospital,
Sapienza University of Rome, Rome, Italy
Received: March 14, 2017; Accepted: April 20, 2017;
Published: April 28, 2017
periodic limb movement disorder (limbs jerking during sleep), which
is an objective physiologic marker of the disorder and is associated
with sleep disruption.
RLS can be caused by low iron levels. Treatment is oen
with levodopa or a dopamine agonist such as pramipexole. Some
controversy surrounds the marketing of drug treatments for RLS. It
is a “spectrum” disease, with some people experiencing only a minor
annoyance and others suering major sleep disruption and impaired
quality of life.
PANDAS is an acronym for Pediatric Autoimmune
Neuropsychiatric Disorders Associated with Streptococcal infections,
a hypothetical subset of conditions in which children are thought
to exhibit an extremely abrupt onset of Obsessive-Compulsive

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Disorder (OCD) and/or tic disorders symptoms following Group A
Beta-Hemolytic Streptococcal (GABHS) infections, with a relapsing-
remitting (not waxing-waning) course [1]. e proposed link between
the infection and these disorders is that an initial autoimmune
reaction to a GABHS infection produces antibodies that continue to
interfere with basal ganglia function, causing symptom exacerbation
[2,3]. e PANDAS hypothesis was based on observations in clinical
case studies at the US National Institute of Health and in subsequent
clinical trials where children appeared to have dramatic and sudden
OCD exacerbations and tic disorders following infection [4]. ere
is supportive evidence for the link between streptococcal infection
and onset in some cases of OCD and tics, but proof of causality has
remained elusive [5-7]. e PANDAS hypothesis is controversial;
whether it is a distinct entity diering from other cases of Tourette
Syndrome (TS)/OCD is debated [3,8-11]. It has not been validated as
a disease entity [4] and is not listed as a diagnosis in the International
Statistical Classication of Diseases and Related Health Problems
(ICD) or the Diagnostic and Statistical Manual of Mental Disorders
(DSM).
Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) was
proposed in 2012 to describe another subset of acute-onset OCD cases
including “not only disorders potentially associated with a preceding
infection, but also acute-onset neuropsychiatric disorders without an
apparent environmental precipitant or immune dysfunction” [12].
We report on a boy in whom restless leg syndrome was an atypical
presentation of PANDAS.
Case Presentation
A 7 year-old boy came to our attention through a pediatric
allergologic visit because for about a year he had suered from
intense itching localized predominantly in the feet and ankles, mainly
occurring while falling asleep but that was still present throughout
the day, forcing him to make continuous movements and stereotyped
patterns of rotation of the limbs in order to nd relief. His family
history was unremarkable. Before coming to our attention, he had
undergone cardiologic assessments (cardiologic examination,
electrocardiogram test and echocardiography) and neurologic
evaluations electroencephalogram, somatosensory evoked potential,
motor evoked potentials, polysomnography and medullary magnetic
resonance imaging) in another hospital: these were all normal. Blood
tests showed only mild hypereosinophilia, elevated Antistreptolysin
O antibody (ASO) titers (ASO 329IU/ml) and low iron levels. He was
discharged with the diagnosis of “Restless Legs Syndrome” (RLS) and
began therapy with gabapentin 100mg twice daily and iron, without
benet.
During our rst check-up, the boy described his problem not as
itchy but as a “deep discomfort” that compels him to move not only
his ankles but also his wrists, with continuous nocturnal awakenings.
Physical examination and skin prick tests were negative. Suspecting
movement disorders associated with GABHS infection, we decide to
repeat the blood tests, particularly ASO (525IU/ml) and neuronal
antibodies (normal levels), and to prescribe azithromycin, rst daily
for 5 days, then weekly for 8 weeks. ere was a clear improvement
in symptoms during the rst month of therapy, and then a new
exacerbation. Blood tests showed an increase in ASO titer (678IU/
ml) and physical examination showed hyperemia of the pharynx that
was not present at the rst examination. At this point we decide to
change the therapeutic approach and started administration of benzyl
penicillin every 20 days, until the next follow-up. Aer three months
of follow-up the boy’s disorders had disappeared and the ASO titer
was stable. e boy was in good clinical condition and no other
movement disorders had appeared.
Discussion
e term PANDAS (Pediatric Autoimmune Neuropsychiatric
Disorders Associated With Streptococcal Infections) describes
a subset of pediatric conditions characterized by Obsessive-
Compulsive Disorder (OCD) and/or tic disorders, in which
symptoms worsen following a streptococcal infection such as “strep
throat” and scarlet fever (NIH). ey appear to be neurobiological
disorders that potentially complicate GABHS infections in genetically
susceptible individuals [13]. ere has been extensive debate about
whether or not PANDAS actually exist. Suerers usually have a
dramatic, “overnight” onset of signs and symptoms that include
motor or vocal tics, obsessions and/or compulsions and remission
of neuropsychiatric symptoms during antibiotic therapy [14]. is
denition was formalized in 1998 by Swedo [15] and collaborators
in a set of ve criteria, of which the core feature was the association
between newly diagnosed infections and tics and obsessive-
compulsive symptoms (Table 1). While in Sydenham’s chorea (SC),
the prototypical post-streptococcal neuropsychiatric disorder, anti-
dopamine receptor antibodies might be relevant, in PANDAS this
association is not found and the pathophysiological mechanism
remains undened [16]. Unlike SC, in PANDAS the latency between
GABHS infection and neuropsychiatric onset seems shorter and so
the immune-mediated mechanism probably diers partly from the
mechanism of SC. e remission of symptoms during antibiotic
therapy (generally with penicillin and azithromycin) is more frequent
in PANDAS than in other acute obsessive-compulsive symptoms
and tics. Over the years the need for a reappraisal of the denition
of PANDAS has become evident, given the diculties in consistently
1 Presence of Obsessive-Compulsive Disorder (OCD) and/or tic disorder.
2 Pediatric onset of symptoms (age 3 years to puberty).
3Acute onset and episodic course (relapsing-remitting, not waxing-
waning).
4 Association with neurological abnormalities (chorei form movements).
5Temporal relationship between symptom exacerbations and GABHS
infections.
Table 1: Diagnostic criteria for PANDAS.
1An urge to move the legs usually but not always accompanied by or felt
to be caused by uncomfortable and unpleasant sensations in the legs.
2The urge to move the legs and any accompanying unpleasant
sensations begin or worsen during periods of rest or inactivity such as
lying down or sitting.
3The urge to move the legs and any accompanying unpleasant
sensations are partially or totally relieved by movement, such as walking
or stretching, at least as long as the activity continues.
4The urge to move the legs and any accompanying unpleasant
sensations during rest or inactivity only occur or are worse in the evening
or night than during the day.
5The occurrence of the above features are not solely accounted for as
symptoms primary to another medical or a behavioral condition (e.g.
myalgia, venous stasis, leg edema, arthritis, leg cramps etc.).
Table 2: International Restless Legs Syndrome Study Group consensus
diagnostic criteria for restless legs syndrome.

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and reliably applying their diagnostic criteria in routine clinical
practice [16]. For example, the main issue is dierentiating a true
“inciting” GABHS infection, whether clinical or subclinical, from
GABHS carrier states [14]. In addition, streptococcal infections are
common in childhood and could be just a trigger for the exacerbation
of tics and obsessive-compulsive disorder.
Restless Legs Syndrome (RLS), also known as Willis-Ekbom
disease, is a common pediatric neurologic condition aecting 2-4%
of school-aged children and adolescents [17]. It is characterized by
throbbing, pulling, creeping or other unpleasant sensations in the legs
and an uncontrollable urge to move them. e pediatric diagnostic
criteria were published in 2003, based on the consensus of experts
at a National Institutes of Health workshop. e weakness of these
criteria is their complexity. ey dier from the diagnostic criteria for
RLS in adults (Table 2), even if it is unlikely that the basic underlying
pathophysiology is dierent at dierent ages. e severity of RLS
symptoms ranges from mild to intolerable. Symptoms can come and
go; they are generally worse in the evening and at night and less severe
in the morning, and may cause severe nightly sleep disruption with
impaired quality of life. In most cases, the cause of RLS in unknown.
However, it may have a genetic component and is probably related to
a dysfunction in the brain’s basal ganglia dopamine pathways.
In adults, RLS is oen associated with iron deciency, pregnancy,
chronic renal failure [18,19] and cardiovascular disease [20,21].
Iron deciency and renal failure are also potential aggravating
factors for pediatric RLS [22]. is may be misdiagnosed as growing
pains, a common, benign condition in childhood characterized
by intermittent bilateral leg pain occurring in the late aernoon or
evening; the presence or absence of a need to move, which worsens
with rest, is an important dierential criteria. With respect to the
ocial diagnostic criteria for restless legs syndrome (Table 2), in
children there are some dierences. For example, sore leg muscles
generally get worse with movement, not better, and, although pain is
not a usual description for RLS, children usually use the word “pain”
or “hurts/hurting”, therefore language and cognitive development
determine the applicability of the RLS diagnostic criteria.
Conclusion
To diagnose PANDAS, the proposed criteria must be fullled.
Evidence of GABHS infection includes a positive throat culture for
GABHS or elevated or increasing antibody titers (ASO, antiDNAse
B) demonstrating a recent GABHS infection. In our case, the throat
culture was negative but ASO titers were very high. Furthermore, the
boy started to experience restless legs syndrome - probably triggered
by a recent streptococcal infection, as evidenced by the high ASO
titers. e persistence of the elevated ASO titers can probably be
explained by the long duration of the infection and the misdiagnosis
on its onset. Intact, our patient did not respond to the standard drugs
for RLS, but his symptoms disappeared with antibiotic therapy.
is case highlights the importance of dierential diagnosis in
patients with streptococcal infection and neurological symptoms.
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