upper MNL

1. Flaccid Paralysis
Dr.MahmoudAboud Elsawy
Master student.

2. 2
Differential
Diagnosis of
Acute Flaccid
Paralysis
 Brainstem stroke
 Brainstem encephalitis
 Acute anterior poliomyelitis
• Caused by poliovirus
• 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)

3. 3
THANKS
ANATO
MIC
REGION
CORRESPONDING DISORDERS
Central
nervou
s
system
—brain
o Brain tumor
o Trauma (accidental, nonaccidental)
o Infection (meningitis, encephalitis,
abscess, congenital infection)
o Ischemia (arterial or venous)
o Hemorrhage
o Demyelinating disease
o Metabolic disease (leukodystrophy;
inborn error of metabolism;
mitochondrial encephalomyopathy,
lactic acidosis, and stroke like
episodes)
o Degenerative disease
o Hemiplegic migraine
o Toxins
o Electrolyte disorders
o Functional neurologic
symptom
o disorder (conversion
disorder)
Central
nervous
system
—spinal
cord
 Transverse myelitis
 Tumor
 Abscess
 Trauma
 Infarction
 Myelomeningocele
 Tethered cord
Central Disorders Causing Weakness in Infants and
Children

4.  Myasthenia gravis (juvenile,
transientneonatal, congenital)
 Botulism
4
Anterior
horn
cell
Peripher
al nerve
Neuromuscul
ar junction
muscl
e
Peripheral Disorders
Causing Weakness in Infants
and Children
 Spinal muscular
atrophy
 Poliomyelitis

6. 6
Demyelinating
Disorders
of the CNS
 Acquired demyelinating disorders of the (CNS) collectively are rare
disorders occurring with an annual incidence of 0.5-1.66 per 100,000
children.
 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.

7. 7
Demyelinating
Disorders
of the CNS
 Pediatric demyelinating syndromes are characterized clinically by
 (1) localization of neurologic deficits (i.e., a single site, such as the spinal
cord [transverse myelitis, TM], versus a polyregional demyelination);
 (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).

8. 8
Acute
Disseminated
Encephalomyeli
tis

9. 9
Transvers
e Myelitis
 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 pleocytosis (>10 cells), or
an increased immunoglobulin G (IgG)
index. The progression is than 21
days.

10. 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.

11. 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.

12. Toxic and Metabolic
Neuropathies

13. Distinguishing Features of Disorders of the Motor System
(Except Genetic)
13

14. Pattern of Weakness and Localization in the
Floppy Infant
14

15. 15

16. 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
16
Spinal Muscular
Atrophies

17. • 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.
Clinical
Classification
17

18. • 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.)
18

19. Clinical Classification of Spinal Muscular
Atrophy
19

20. 20
• 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.
ETIOLOGY
?

21. 21
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.

22. • 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.
DIAGNOSIs
22

23. • 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.
GENETIC
S

25. 2
5
THANK
YOU

26. ● Nelson Essentials of Pediatrics 9th Edition 2023
● Illustrated textbook of pediatrics.
● Uptodate: Etiology and evaluation of the child with
weakness.
26
REFERENCES
• Medstudy neurology chapter.
● 26- XXVI The Nervous System, 27- XXVII Neuromuscular
Disorders from Nelson 21th ed,

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THANKS