Flaccid Paralysis

Dr.Mahmoud Aboud Elsawy

Master student.
 Differential ❑ Brainstem stroke
❑ Brainstem encephalitis
Diagnosis of Acute ❑ Acute anterior poliomyelitis
• Caused by poliovirus
Flaccid Paralysis • Caused by other neurotropic viruses
• Unknown cause of acute flaccid myelitis
❑ Acute myelopathy
• Space-occupying lesions
• Acute transverse myelitis
❑ Peripheral neuropathy
• Guillain-Barré syndrome
• Post–rabies vaccine neuropathy
• Diphtheritic neuropathy
• Heavy metals, biologic toxins, or drug intoxication
• Acute intermittent porphyria
• Vasculitic neuropathy
• Critical illness neuropathy
• Lymphomatous neuropathy
❑ Disorders of neuromuscular transmission
• Myasthenia gravis
• Biologic or industrial toxins
• Tic paralysis
❑ Disorders of muscle
• Hypokalemia
• Hypophosphatemia
• Inflammatory myopathy
• Acute rhabdomyolysis
• Trichinosis
• Familial periodic paralyses (normokalemic, hypokalemic, hyperkalemic)
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Central Disorders Causing Weakness in Infants and Children
ANATO CORRESPONDING DISORDERS
MIC
REGION

Central o Brain tumor o Degenerative disease

nervou o Trauma (accidental, nonaccidental) o Hemiplegic migraine
s
system
—brain
abscess, congenital infection)
o Ischemia (arterial or venous)
o Hemorrhage
THANKS
o Infection (meningitis, encephalitis, o
o
o
Toxins
Electrolyte disorders
Functional neurologic
symptom
o Demyelinating disease o disorder (conversion
o Metabolic disease (leukodystrophy; disorder)
inborn error of metabolism;
mitochondrial encephalomyopathy,
lactic acidosis, and stroke like
episodes)

Central ✓ Transverse myelitis ✓ Infarction

nervous ✓ Tumor ✓ Myelomeningocele
system ✓ Abscess ✓ Tethered cord
—spinal ✓ Trauma
cord

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Peripheral Disorders Causing
Weakness in Infants and Children

Anterior Neuromuscular
Peripheral
horn cell nerve
junction muscle

➢ Myasthenia gravis (juvenile,

❑ Spinal muscular atrophy transientneonatal, congenital)
❑ Poliomyelitis ➢ Botulism

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Demyelinating ❑ Acquired demyelinating disorders of the (CNS) collectively are rare
Disorders disorders occurring with an annual incidence of 0.5-1.66 per 100,000
children.
of the CNS
❑ They present with neurologic dysfunction caused by immune-mediated
attacks on the white matter insulating the brain, optic nerves, and spinal
cord.
❑ The white matter insulation is formed by myelin contained within
oligodendrocytes wrapping around nerve axons.
❑ There are two IgG antibodies recognized as playing an important role in
demyelination, aquaporin 4-antibody (AQP4-Ab) and myelin
oligodendrocyte glycoprotein antibody (MOG-Ab).
❑ The aquaporins, plasma membrane water-transporting proteins, are
expressed in astrocytes and involved in water movement, cell migration,
and neuroexcitation.
❑ Myelin oligodendrocyte glycoprotein is exclusively expressed in the
CNS, and although it is only a minor component of the myelin sheath, its
location on the outermost lamellae and on the cell surface of
oligodendrocytes makes it available for antibody binding.
❑ Increased awareness of the importance of these antibodies, together
with available disease-modifying treatments (DMTs) has made accurate
diagnosis in demyelinating disorders crucial.
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Demyelinating ❑ Pediatric demyelinating syndromes are characterized clinically by
Disorders ➢ (1) localization of neurologic deficits (i.e., a single site, such as the spinal
cord [transverse myelitis, TM], versus a polyregional demyelination);
of the CNS ➢ (2) the presence or absence of encephalopathy;
➢ (3) the disease course (i.e., monophasic versus repeated attacks involving
either the same region or new CNS regions); and
➢ (4) the presence or absence of specific antibodies.
❑ MRI of the brain and spine characterize both symptomatic and clinically
silent lesions, aid in diagnosis, and predict the recurrence.
❑ Serial MRIs may be needed to confirm the diagnosis and monitor the
treatment response and guide the escalation of a DMT.
❑ The presence of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF)
analysis is used to confirm the diagnosis of multiple sclerosis (MS);
their absence may suggest an alternative diagnosis.
❑ Additional studies, including an autoimmune profile, antibody testing, metabolic
testing, genetic testing, catheter angiography, and sometimes even brain biopsy,
may be required to evaluate for mimics of demyelination,
❑ The majority of children are monophasic; they do not relapse.
❑ Monophasic demyelinating disorders of childhood include acute
disseminated encephalomyelitis (ADEM), optic neuritis (ON), and
transverse myelitis (TM); relapsing forms of demyelination include MS
and neuromyelitis optica spectrum disorder (NMOSD).
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 Acute
Disseminated
Encephalomyelitis

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❑ Transverse myelitis (TM) is a
condition characterized by rapid
development of both motor and
sensory deficits at any level of spinal
cord.
❑ TM presents acutely as either partial
or complete cord involvement with
bilateral signs and in adults and
older children with a clear sensory
level.
❑ TM has multiple causes and can be
idiopathic or secondary to either an
immune-mediated condition (postinfectious
or antibody driven) or as a result of direct
infection (infectious myelitis).
❑ In TM, evidence of spinal cord inflammation
can be demonstrated by an MRI-
documented–enhancing lesion, CSF
Transverse pleocytosis (>10 cells), or an increased
immunoglobulin G (IgG) index. The
Myelitis progression is than 21 days.
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Hemiplegic migraine is one of the better-known forms of rare auras.
This transient unilateral weakness usually lasts only a few hours but may persist for days.
Both familial and sporadic forms have been described.
The familial hemiplegic migraine is an autosomal dominant disorder with mutations
described in three separate genes: CACNA1A, ATP1A2, and SCN1A.
Some patients with familial hemiplegic migraine have other yet-to-be-identified genetic
mutations.
Multiple polymorphisms have been described for these genes.
Hemiplegic migraines may be triggered by minor head trauma, exertion, or emotional stress.
The motor weakness is usually associated with another aura symptom and may progress
slowly over 20-30 min, first with a visual aura and then, in sequence, with sensory, motor,
aphasic, and basilar auras.
Headache is present in more than 95% of patients and usually begins during the aura;
headache may be unilateral or bilateral and may have no relationship to the motor
weakness.
Some patients may develop attacks of coma with encephalopathy, cerebrospinal fluid (CSF)
pleocytosis, and cerebral edema.
Long-term complications may include seizures, repetitive daily episodes of blindness,
cerebellar signs with the development of cerebellar atrophy, and mental retardation.
Leukodystrophies
Several hereditary degenerative diseases of white matter of the central nervous system also
cause peripheral neuropathy.
The most important are Krabbe disease (globoid cell leukodystrophy), metachromatic
leukodystrophy, and adrenoleukodystrophy.
Within the brain, they produce progressive but selective demyelination, affecting the deep
white matter of the centrum semiovale with relative sparing of U-fibers around each gyrus.
KRABBE DISEASE (GLOBOID CELL LEUKODYSTROPHY)
a rare autosomal recessive neurodegenerative disorder characterized by severe myelin loss
and the presence of globoid bodies in the white matter.
The gene for KD (GALC) is located on chromosome 14q24.3-q32.1.
The disease results from a marked deficiency of the lysosomal enzyme galactocerebroside β-
galactosidase (GALC).
KD is a disorder of myelin destruction rather than abnormal myelin formation.
METACHROMATIC LEUKODYSTROPHY
This disorder of myelin metabolism is inherited as an autosomal recessive trait and is
characterized by a deficiency of arylsulfatase A activity.
The ARSA gene is located on chromosome 22q13.33.
The absence or deficiency of arylsulfatase A leads to accumulation of cerebroside sulfate
within the myelin in both the central and peripheral nervous systems because of the inability
to cleave sulfate from galactosyl-3-sulfate ceramide.
The excessive cerebroside sulfate is thought to cause myelin breakdown.
Toxic and Metabolic Neuropathies
Distinguishing Features of Disorders of the Motor System (Except Genetic)

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Pattern of Weakness and Localization in the Floppy Infant

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Spinal Muscular Atrophies
INTRODUCTION
❑ Spinal muscular atrophy (SMA) is a degenerative disease of motor
neurons that begins in fetal life and continues to be progressive in
infancy and childhood.
❑ Among the autosomal recessive disorders in childhood, SMA is the
most common cause of infant mortality, and is second in birth
prevalence only to cystic fibrosis.
❑ The incidence of SMA is estimated to be 1 in 6,000-10,000
newborns, with a carrier frequency of approximately 1/40-
1/60.
❑ It is a clinically heterogeneous, panethnic disorder.
❑ SMA is caused by a homozygous deletion in the survival
motor neuron 1 (SMN1) gene on chromosome 5q13.
❑ Infrequent families with autosomal dominant inheritance are
described, and a rare X-linked recessive form also occurs.
❑ There is also a separate group of clinically and genetically
heterogeneous non-5q SMA forms

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Clinical Classification

• SMA is classified clinically into a severe infantile form, also known

as Werdnig-Hoffmann disease or SMA type I;
• a late infantile and more slowly progressive form, SMA type II;
• a more chronic or juvenile form, Kugelberg-Welander disease, or
SMA type III;
• and an adult-onset form (SMA type IV).
• A severe fetal form that is usually fatal in the perinatal period has
been described as SMA type 0, with motor neuron degeneration
demonstrated in the spinal cord as early as midgestation.
• These distinctions of types are based upon the age at onset,
severity of weakness, maximum motor milestone achieved, and
clinical course .
• Although there is a correlation between the severity of disease,
age at onset, and SMN2 copy number to an extent, it is believed
that the phenotype of SMA spans a broad continuum without a
clear delineation of subtypes.

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• Type 1 spinal muscular atrophy (Werdnig-
Hoffmann disease).
• Characteristic postures in 6 wk old (A) and 1
yr old (B) infants with severe weakness and
hypotonia from birth.
• Note the frog-leg posture of the lower limbs
and internal rotation (“jug handle”) (A) or
external rotation (B) at the shoulders.
• Note also intercostal recession, especially
evident in B, and normal facial expressions.
• (From Volpe J: Neurology of the newborn, ed
4, Philadelphia, 2001, WB Saunders, p. 645.)

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Clinical Classification of Spinal Muscular Atrophy

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 ETIOLOGY ?

• The cause of SMA is genetic as an autosomal recessive mendelian trait.

• It appears to be a pathologic continuation of a process of programmed cell death (apoptosis) that is
normal in embryonic life.
• A surplus of motor neuroblasts and other neurons is generated from primitive neuroectoderm, but only
about half survive and mature to become neurons; the excess cells have a limited life cycle and
degenerate.
• The survivor motor neuron gene (SMN) arrests apoptosis of motor neuro-blasts.
• Unlike most genes that are highly conserved in evolution, SMN is a uniquely mammalian gene.
• An additional function of SMN, both centrally and peripherally, is to transport RNA-binding proteins to
the axonal growth cone to ensure an adequate amount of protein-encoding transcripts essential for
growth cone mobility, both during fetal development and in postnatal synaptic remodeling.
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CLINICAL MANIFESTATIONS AND COURSE
• The cardinal features of the
classic, most common phenotype,
type I, can be summarized as a
presentation before the age of 6
mo with severe hypotonia;
symmetric generalized muscle
SMA weakness affecting the lower
limbs more than the upper limbs,
proximal more than distal; frog-leg
posture; absence of deep tendon
reflexes; tongue fasciculations;
and selective involvement of the
axial and intercostal muscles but
sparing of diaphragm.
• SMA is in the differential diagnosis
list of floppy infant syndrome.
• Due to the involvement of the
intercostal respiratory muscles,
there is a typical paradoxical
abdominal breathing pattern, bell-
shaped chest, and weak cough.
• Infants lie flaccid with little movement,
unable to overcome gravity, and lack
head control. These infants rarely achieve
improvements of motor function and
acquire motor developmental milestones.
• In contrast to their severe weakness and
floppiness, infants with SMA type I have
an alert and bright expression with
preserved cognitive functions.
• There is no involvement of the facial and
extraocular muscles at presentation,
although facial weakness does occur at
later stages of the disease.
• SMA type I is not homogeneous
within itself.
• At least three clinical subgroups can
be defined as
• (1) severe weakness from birth or
the neonatal period; head control is
never achieved;
• (2) presentation after the neonatal
period, within the first 2 mo; head
control is never achieved; and
• (3) onset after the neonatal period
but head control is achieved, and
some of the infants may gain the
ability to sit with support.
• There may be a range of clinical
presentations and courses of
respiratory involvement and
swallowing and sucking difficulties
in this fragile group of SMA type I
patients.
• Infants with SMA type I develop
respiratory failure within the first 2
yr of life, and without respiratory
and nutritional support, they usually
do not survive beyond their second
birthday.
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DIAGNOSIs
• The simplest, most definitive first-step diagnostic test in a patient with a clinical suspicion of SMA and
normal and/or mildly elevated serum CK levels, is a molecular genetic marker in the blood for the
homozygous deletion in SMN1.
• The current gold standard is SMN1 deletion/mutation and SMN2 copy number testing, with a minimal
standard of SMN1 deletion testing.
• The absence of SMN1 exon 7 (with or without deletion of exon 8) confirms the diagnosis of SMA.
• The genetic test for SMA has a 95% sensitivity and nearly 100% specificity.
• Real-time polymerase chain reaction (PCR) or multiplex ligation-dependent probe amplification
(MLPA) tests give quick and reliable SMN1 gene copy numbers.
• Semiquantitative assays improve the diagnostic sensitivity up to 98%.
• According to different scenarios, for example, if the patient has a single SMN1 copy, the coding region
of the second undeleted allele should be sequenced to identify the second causative mutation,
including point mutations, insertions, and deletions.
• Of note, in ~ 30% of patients with a clinical picture, mutations are not detected in the SMN1/SMN2
coding region, which is more common for type III SMA patients.
• Direct sequencing of the gene is also recommended in patients with a clinical diagnosis, two SMN1
copies, and a consanguineous background.

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 GENETICS

• Molecular genetic diagnosis by DNA probes in blood samples or in muscle

biopsy or chorionic villi tissues is available for the diagnosis of suspected
cases and for prenatal diagnosis.
• Most cases are inherited as an autosomal recessive trait.
• The genetic locus for all three of the common forms of SMA is on
chromosome 5, a deletion at the 5q11-q13 locus, indicating that they are
variants of the same disease rather than different diseases.
• The affected SMN1 gene has a molecular weight of 38 kDa and contains 8
exons that span 20 kb and telomeric and centromeric exons that differ
only by 5 bp and produce a transcript encoding 294 amino acids.
• SMN1 is duplicated in a highly homologous gene called SMN2, and both
genes are transcribed.
• SMN2 remains present in all patients with SMA, but cannot fully
compensate the SMN1 defect.
• However, a molecular basis for correlation between the SMN2 copy
number and clinical severity of the SMA is the capability of SMN2 to
encode a small amount of an identical SMN protein.
• The critical difference between SMN1 and SMN2 is a cytosine (C) to
thymine (T) transition in exon 7 of SMN2.
THANK
YOU

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REFERENCES
● Nelson Essentials of Pediatrics 9th
Edition 2023

● Illustrated textbook of pediatrics.

● Uptodate: Etiology and evaluation of

the child with weakness.

● 26- XXVI The Nervous System, 27- XXVII

Neuromuscular Disorders from Nelson 21th
ed,

• Medstudy neurology chapter.

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THANKS

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