Introduction. Neuroanatomy Signs and Symptoms. Disorders: Primary Lateral Sclerosis. Hereditary Spastic Paraplegia. Human T-Lymphotropic Virus Type 1-Associated Myelopathy, or Tropical Spastic Paraparesis. Human T-Lymphotropic Virus Type 2-Associated Myelopathy. Adrenomyeloneuropathy. Plant Excitotoxins.

1. DISORDERS OF
UPPER MOTOR
NEURONS
By / Lobna Ahmed

2. Outlines
• Introduction.
• Neuroanatomy
• Signs and Symptoms.
• Disorders:
 Primary Lateral Sclerosis.
 Hereditary Spastic Paraplegia.
 Human T-Lymphotropic Virus Type 1-Associated Myelopathy, or Tropical Spastic
Paraparesis.
 Human T-Lymphotropic Virus Type 2-Associated Myelopathy.
 Adrenomyeloneuropathy.
 Plant Excitotoxins.

3. Introduction
• Motor neuron diseases include a variety of acquired and inherited
neurodegenerative conditions that entirely or predominantly injure motor
neurons.
• Amyotrophic lateral sclerosis (ALS) is the most common of these
diseases .
• The motor neuron system is composed of upper and lower motor neurons.
• Upper motor neurons reside in the primary motor cortex of the brain, and
their axons comprise the corticobulbar tract (connecting to the brainstem)
and the corticospinal tract (connecting to the spinal cord).

4. • Lower motor neurons, also referred to as alpha motor neurons or anterior
horn cells, are located in motor nuclei in the brainstem or the anterior gray
matter of the spinal cord. Their axons connect to muscles of the bulbar
region or limbs.
• Injury to the motor neuron system results in loss of voluntary muscle
function that may affect limb, bulbar, and/or respiratory function, with the
specific symptoms depending on which part of the motor pathway is affected.

5. https://doi.org/10.3389/fnhum.2016.00638
The
Change
of
Intra-cerebral
CST
Location
during
Childhood
and
Adolescence;
Diffusion
Tensor
Tractography
Study

7. Signs and Symptoms
Loss of
dexterity
Loss of muscle
strength
Spasticity
Hyperreflexia &
pathological
reflexes
Pseudobulbar
palsy

8. -The most characteristic signs of UMN impairment.
-Manifest as stiffness, slowness, and clumsiness in
performing any skillful motor actions.
-Asking the patient to perform rapid repetitive motions such as foot or finger tapping assesses loss of
dexterity at the bedside.
-It is useful to assess both sides of the body.
-Generally mild.
-Extensor muscles of the UL and flexor muscles of the LL may become weaker than their antagonist
muscles.
(UMN lesion disinhibits brainstem control of the vestibulospinal and reticulospinal tracts).

9. -The Babinski sign (extensor plantar response) is perhaps the most important sign in the clinical
neurological
examination .
-This sign may only evolve at a later stage of disease and may be absent in the setting of marked
atrophy of the toe extensor muscles.
-Spastic bulbar palsy due to involvement of the corticobulbar tracts that exert supranuclear control
over those motor nuclei that control speech, mastication, and deglutition.
-The prefix pseudo distinguishes this condition from true bulbar palsy that results from pure LMN
involvement in brainstem motor nuclei.
-Articulation, mastication, and deglutition are impaired in both pseudobulbar and bulbar palsies, but
the degree of impairment in pseudobulbar palsy is generally milder.
-Spontaneous or unmotivated crying and laughter uniquely characterize pseudobulbar palsy. This is
also termed emotional lability, hyperemotionality, labile affect, or emotional incontinence.

10. Primary Lateral
Sclerosis

11. • Primary lateral sclerosis (PLS), first described by Erb in 1875, is a rare
UMN disease variant that accounts for 2% to 4% of all cases of ALS.
• Distinguished from ALS by restricted involvement of UMN for at least 3
years from the time of clinical onset. However, a figure of 4 years is now
proposed during which there is neither clinical nor neurophysiological
evidence of LMN involvement.
• Nonetheless, later development of LMN signs may occur and require
reclassification as ALS in some cases, which therefore necessitates constant
longitudinal review of each case.

12. Clinical presentation
• Typically presents in patients in their early 50s (about a decade younger
than typical MND/ALS patients).
very slowly evolving that
spreads to the upper limbs
and eventually causes
pseudobulbar palsy.
Bulbar-onset
Mills hemiplegic
variant
Spastic Paraparesis
should prompt looking for
later LMN signs elsewhere.
In rare instances, onset is in
the bulbar system or follows
a slowly ascending or
descending hemiplegic
pattern

13. Other
features Cramps and
fasciculations
Muscle atrophy
Subtle cognitive
deficits
Abnormal voluntary
eye movements
Bladder dysfunction
Late
Secondary to frontal cortical involvement, but
dementia is not a prominent feature.

14. Pathology
• The underlying pathogenesis of PLS
remains undefined.
• Pathological changes include a
striking loss of Betz cells in layer 5 of
the frontal and prefrontal motor
cortex (and other smaller pyramidal
cells) together with laminar gliosis of
layers 3 and 5 and degeneration of the
corticospinal tracts.
• Spinal anterior horn cells are
characteristically unaffected.
Prognosis
• The prognosis is significantly better
than for MND/ALS.
• one series had a median disease
duration of 19 years and another
series exhibited a range of survival
from 72 to 491 months.

15. Diagnosis
• Must exclude all definable causes for generalized UMN involvement.
Structural
abnormalities
 Chiari malformation.
 Intrinsic and extrinsic
spinal cord lesions).
Myelopathies
 Multiple sclerosis.
 Spondylotic cervical
myelopathy.
 HIV myelopathy.
 Human T-lymphotropic
virus type 1 (HTLV-1)
myelopathy.
 Lyme disease.
 Syphilis.
 Adrenomyeloneuropathy.
Hereditary
 Hereditary spastic
paraplegia (HSP)/familial
spastic paraparesis.
 Spinocerebellar ataxia
(SCA).
 Hexosaminidase-A (Hex-A)
Deficiency.
 Familial ALS (FALS).
 Adrenomyeloneuropathy.

16. Treatment
• No specific pharmacotherapy is available.
• Treatment focuses on symptom control and supportive care.
• Anti-spasticity drugs such as the GABA-B agonist, baclofen, and the central
α2-agonist, tizanidine, may be tried for symptomatic treatment.
• Severe spasticity sometimes requires the insertion of an intrathecal baclofen
pump.
• Tricyclic antidepressants, selective serotonin reuptake inhibitors, or
dextromethorphan/quinidine may control pseudobulbar affect lability

17. Hereditary Spastic
Paraplegia

18. HSP (or familial spastic paraparesis) is a genetically and clinically
heterogeneous group of disorders.
Common features
Progressively worsening
spasticity of the lower
extremities, often with variable
degrees of weakness
The characteristic pathology is
retrograde degeneration of the
longest nerve fibers in the
corticospinal tracts and
posterior columns.

19. • The most common mode of inheritance is autosomal dominant, but it may also be
inherited in a recessive or X-linked fashion, and also reported 13–40% of cases being
sporadic (ie, with no family history).
• Inheritance of most pure HSP is autosomal dominant, whereas complicated forms are
more often autosomal recessive.
• onset is from infancy into the eighth decade, however most cases present in the second
to fourth decades.
• The clinical syndrome is broadly divisible into:
The pure form >>patients develop only lower-extremity spasticity, but some of these
cases eventually become complicated.
The complicated form.

20. Pure form
Up to 25% of affected patients are
asymptomatic, emphasizing the often
benign nature of the disease and the
importance of careful clinical evaluation
of families included in genetic studies.
A characteristic feature of HSP is the
marked discrepancy between the often
severe spasticity and only mild or absent
muscle weakness.

21. Complicated form
Optic neuropathy, pigmentary retinopathy, deafness.
Ataxia, amyotrophy, peripheral neuropathy.
Dementia.
Extrapyramidal dysfunction.
Intellectual disability.
Bladder dysfunction.
Autoimmune hemolytic anemia/thrombocytopenia.
Ichthyosis.

23. Genetics
• Novel techniques such as
exome sequencing are
valuable in discovering new
genes.
• The genetic classification is
based on sequential
numbering of chromosomal
loci or specific genes, as they
were identified, using a
spastic paraplegia gene
(SPG) designation.
• Up to 79 SPG genes have been
described so far. Many of these
have only been identified in
single families.
• At present, mutations in four
genes; L1CAM, PLP, paraplegin,
and spastin have been identified
as playing a part in the
development of an HSP
phenotype.

25. SPG4 and SPG3A were the most frequent autosomal dominant hereditary spastic paraplegia
(HSP), while SPG11 followed by SPG7 were the most frequent autosomal recessive HSP.

26. Diagnosis
Family
Hx
Progressive
gait
disturbance
LL
spasticity
Sparing of
cortico-
bulbar
functions
HSP
-In the absence of a family
history or a demonstration
of a known mutation, it is
important to consider
alternative causes for the
clinical presentation.
-MRI may reveal that cervical and thoracic spinal cord diameters are
significantly smaller in both pure and complicated HSP than in
controls.
-There are occasional reports of mild to moderate atrophy of
intracranial structures, particularly the corpus callosum, and also of
white matter lesions in the cerebral hemispheres.

28. Hereditary
spastic
paraplegia:
from
diagnosis
to
emerging
https://doi.org/10.1016/S1474-
4422(19)30235-2

29. Deferential diagnosis

30. Treatment
• At present, treatment of spastic paraplegia is limited to symptomatic interventions, supportive
care to reduce spasticity, and appliances and orthotics such as canes, walkers, and wheelchairs.
• Anti-spasticity drugs such as baclofen, tizanidine, diazepam, and dantrolene are often suboptimal,
and patients with very disabling spasticity may require intrathecal baclofen administered through
an implanted pump.

31. Human T-Lymphotropic
Virus Type 1-Associated
Myelopathy
(Tropical Spastic Paraparesis)

32. • HTLV-1 causes a chronic progressive myelopathy that is referred to as tropical spastic paraparesis
(TSP) in the Caribbean or HTLV-1–associated myelopathy (HAM) in Japan.
• While between 2% and 3% of those infected can develop adult-onset T-cell leukemia, an estimated
2.5% to 3.8% can develop a chronic inflammatory myelopathy.
• Mode of transmission is through contaminated blood, sexual activity, breastfeeding, and very
rarely in utero.
• HAM/TSP is a chronic, insidiously progressive myelopathy that typically begins after age 30 years
(but can occur as early as the first decade).

33. Slowly
progressive
paraparesis
LL
paresthesia
Painful
sensory
neuropathy
Bladder
dysfunction
Optic
neuropathy
Clinical presentation

34. Examination
• Reveals UMN signs in the legs (weakness, spasticity, pathological reflexes, hyper-reflexia), although
reflexes may also be brisk in the arms.
• Overall, evidence of LMN involvement may be scant.
• Objective sensory findings may be difficult to detect.

35. Investigations
MRI
-The most common imaging feature of HTLV-1 associated
myelopathy is cord atrophy and increased signal, seen in three-
quarters of affected individuals.
-This is most pronounced in the lateral columns, mostly involving
white matter, but also involving nearby grey matter and anterior
nerve roots.
-Over half of affected individuals will also demonstrate high T2
signal in the cerebral white matter.

37. The definitive diagnosis of HAM/TSP requires HTLV-1–positive serology in
blood and cerebrospinal fluid (CSF).

38. Human T-Lymphotropic
Virus Type 2-Associated
Myelopathy

39. • HTLV-1 and HTLV-2 are antigenically distinct. Nonetheless, using ELISA and Western blot
techniques, many laboratories worldwide often report the presence of sero-indeterminate HTLV-1/2.
• This retrovirus is endemic in some Native American tribes and now often encountered worldwide
among IV drug abusers >> It is worthwhile to test CSF and serum for the presence of this virus in
known IV drug abusers who present with a spastic paraparesis.
• Rare cases are now being described of a syndrome characterized by spastic paraparesis, diffuse
hyperreflexia, spastic bladder, and periventricular white matter changes on MRI in patients infected
with HTLV-2 but not HTLV-1.
• Coinfection with HIV-1 is a confounding factor in many cases of presumed HTLV-2–associated
neurological disease ( coinfection increases the likelihood of neurological manifestations).

40. Adrenomyeloneuropathy
(AMN)

41. • X-linked adrenoleukodystrophy is a peroxisomal disorder of beta-oxidation that results
in accumulation of very long-chain fatty acids (VLCFAs) in all tissues.
• ALD consists of a spectrum of phenotypes (including adreno-myeloneuropathy [AMN].
• Basically there are three main types that are present in about 90% or 95% of the
affected people:
 A childhood cerebral form.
 Adreno-myeloneuropathy (AMN).
 Adrenal insufficiency-only type.

42. AMN
• Caused by mutations. in the ABCD1 gene and is inherited in an X-linked manner.
• It is a noninflammatory axonopathy of the spinal cord that involves descending corticospinal tracts
in the thoracic and lumbosacral regions and the ascending posterior columns in the cervical region.
• The characteristic clinical picture:
Adult men
(in their late 20s)
Slowly progressive
spastic
paraparesis
Mild
polyneuropathy
+/- Sphincter
disturbances.
+/- Sensory
symptoms

43. • Adrenal insufficiency may be present and may predate onset of neurological symptoms by several
years.
• Adult female carriers may present with an age-related slowly progressive spastic paraparesis.
• Approximately 20% of men with adreno-myeloneuropathy also develop cerebral changes on MRI
that may accompany cognitive / language / behavioral deterioration.
• Rare cases may present as a spinocerebellar degeneration.
• Considerable phenotypic variation exists even within individual families. Female carriers may
manifest more subtle symptoms such as cramps, back pain, or arthralgias.

44. When to suspect
AMN
Male cases with progressive
sensorimotor deficits in the legs and
a family history of a myelopathy
(including supposed MS).
Progressive sensorimotor deficits in
the lower extremities with a history of
memory loss or “attention deficit
disorder.”
A history of idiopathic childhood
epilepsy or primary adrenal failure.

45. Investigations
• Sural nerve biopsies show loss of both myelinated and unmyelinated axons, with some
degree of onion bulb formation.
• Nerve conduction studies and needle EMG may reveal a predominantly axon-loss type
of sensorimotor polyneuropathy with a lesser component of demyelination.
• SSEPs may show reduced or absent responses.
• There may be signal abnormalities seen in the corticospinal tracts and parieto-occiptal
white matter on MRI.

47. Increased VLCFA in
plasma, RBC, or
cultured skin
fibroblast.
The diagnostic
test of choice

48. Plant Excitotoxins

49. Lathyrism
• A chronic toxic nutritional neurological disease
caused by long-term (or subacute) ingestion of
flour made from the drought-resistant chickling
pea (Lathyrus sativus).
• An important example of a disease in which a
natural excitotoxin causes selective UMN
impairment.
• The responsible neurotoxin is β-N-oxalylamino-
l-alanine (BOAA).

50. • Lathyrism occurs in the indigenous populations of Bangladesh, China, Ethiopia, India, Romania,
and Spain.
• May occur in epidemic form when malnourished populations increase consumption of flour made
from L. sativus chickling peas during times of food shortage due to droughts.
• Acute or chronic onset of muscle spasms, cramps, and leg weakness. In addition to spastic
paraparesis, sensory and bladder dysfunction may occur.
β-N-oxalylamino-l-
alanine (BOAA)
AMPA glutamate
receptor agonist
Increased intracellular
levels of reactive
oxygen species

51. • Konzo (“tied legs”) is another toxic nutritional disorder of
cortical motor neurons.
• Caused by chronic dietary ingestion of a neurotoxin derived
from flour made from cassava roots that have not been soaked
for a sufficient time.
• The disorder is endemic in protein-deficient communities in
Tanzania, Zaire, and Eastern Africa.
• At times of famine can occur in epidemic form.
konzo

52. • As with lathyrism, there appears to be a selective effect on Betz cells of the cerebral cortex and the
longest corresponding corticospinal tracts.
• Patients typically present with spastic paraparesis (although some may exhibit only lower-
extremity hyperreflexia).
• Occasionally one may detect weakness of the upper extremities, but not to the same degree as that
of the lower extremities.
Cyanohydrins Thiocyanate Stimulate the AMPA
glutamate receptor
Excitotoxic
neuronal injury

53. Thank you