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NS II 2016
Pathology III
Dr. Mohammed Alorjani. MD EBP
PARKINSON Disease
 Disturbance of motor function with
tremor, rigidity, slow movements,
expressionless facies and instability
 Damage to Dopaminergic neurons in
Substantia Nigra
• Adults in the 6th.decade
• TYPES of Parkinsonism:
• Idiopathic: Sporadic or familial,
Parkinson disease:  synuclein gene
involved in neuronal synapses
Several other genetic abnormalities
found some related to Tau protein.

Secondary: Trauma, vascular
disorders, viral encephalitis,
neurotoxic agents, drugs
Gross and microscopic findings
 Gross:
loss of pigment in the substantia nigra
 Microscopic:
Loss of pigmented neurons and gliosis
in substantia nigra.
Lewy bodies in remaining neurons
Cortical Lewy bodies may be present in
small numbers in 80% or more of PD cases
 LEWY BODIES:
- Concentric eosinophilic inclusions in the
cytoplasm with surrounding halo.
Contain Presynaptic Protein  synuclein
•
LEWY NEURITES contain abnormal
aggregates of  synuclein
 Lewy bodies can occur anywhere in the brain
& may be numerous:
May occur in medulla & pons before S.N.
Normal
LEWY BODIES
Clinical Features:
 Progress over 10-15 yrs  severe
bradykinesia
 Death usually due to repeated infections or
fall-related trauma
 Initially responds to L-DOPA
 Widespread effect on brain. Other deficits may
precede motor dysfunction
 Lewy body dementia: Dementia that appears
within 1 yr. of onset of motor symptoms
Overlap with Alzheimer...
HUNTINGTON DISEASE
 Hereditary progressive disease
 AD, defect on Ch.4, Huntingtin gene that
contains increased trinucleotide CAG repeat
sequences → Polyglutamine (PolyQ)
 The greater the number of repeats, the
earlier the onset of the disease.
 Age 30 and 50 years, with average course of
15 years to death.
 Symptoms usually appear in middle age
Clinical Presentation:
 Choreiform (dance-like) movements,
Involuntary jerky movements & dementia
Pathology:
 Atrophy of striatum (caudate and putamen),
frontal L.
 Head of the caudate becomes shrunken
 Severe loss of small neurons in the caudate
and putamen with subsequent gliosis.
 Remaining neurons: Nuclear ubiquitinated
Huntingtin protein (+) inclusions.
 There is "ex vacuo" dilatation of the anterior
horns of the lateral ventricles.
Neurons in Degenerative diseases
 Parkinson disease → Accumulation of  synuclein
gene product → neuronal death in S.N. producing
dopamine → difficulty initiating movement.
 Huntington disease → genetic mutation →
overproduction of CAG repeats → death of
neurons in basal ganglia → Choreiform movements
 Alzheimer disease, β amyloid accumulation in and
around neurons in the neocortex and hippocampus
(control memory) → Death of neurons
MOTOR NEURON Diseases
 Amyotrophic Lateral Sclerosis,
(ALS) Lou Gehrig’s disease
• Cause is unknown
• Most are sporadic, 5-10% familial AD
• Several gene mutations implicated,
- most frequent is superoxide
dismutase (SOD-1) on chr. 21
- some with TDP-43 mutation –
! Overlap with FTLD
AMYOTROPHIC LATERAL SCLEROSIS
 Death of motor neurons in spinal cord & brain
stem  painful fasciculation of muscles, with
neurogenic atrophy of the muscles
 Death of upper motor neurons in motor cortex
 paresis, hyperreflexia & spasticity
 Degeneration of corticospinal tracts in lateral
part of spinal cord
 In most cases, ALS does not affect a person's
mental abilities, senses, reasoning, memory, or
personality.
 Later: speech, swallowing, respiratory muscles
affected
 Bowel and bladder control are not impaired.
 Death within 5 years – recurrent respiratory
infections
Lou Gehrig 1903 - 1941
Diagnosed ALS 1938/1939
1942 – alive in 2015
2015 British Academy Film
Awards ceremony at The
Royal Opera House in
London.
 Pathology:
Loss of motor neurons in:
1- Ant. horn cells of spinal cord
2- Brain stem nuclei
3- Upper motor neurons in cerebral cortex
Later, gliosis, axonal degeneration, loss of
myelinated fibres in lateral corticospinal
tracts  muscle atrophy
Acquired Metabolic & Toxic
Disorders
A- Nutritional Diseases:
1- Thiamine deficiency:
Beriberi & alcoholism
 Pathology: Wernicke encephalopathy

hemorrhage in mamillary bodies
hemosiderin deposition

gliosis
 Symptoms

Memory loss

Peripheral neuropathy

2 - Vitamin B12 deficiency
 Pernicious anemia
 Subacute Combined Degeneration of
Spinal Cord
Pathology:
Myelin loss in dorsal & lateral columns
Symptoms:
Result in motor & sensory loss
B- Acquired Metabolic Disorders
 1- Hypoglycemia:
 Changes similar to Global hypoxia
especially in hippocampus.
 Cerebellar Purkinje cells more resistant.
 2- Hyperglycemia:
 Ketoacidosis in uncontrolled Type I
 Hyperosmolar coma in Type II
 Result → coma due to intracellular
dehydration
 Rapid correction → cerebral edema
 3- Liver disease:
 Metabolic dysfunction of astrocytes →
inability to detoxify accumulated
ammonia → Hepatic Encephalopathy and
‘Flapping tremor’
Pathology :
Glial response with
formation of
Alzheimer type II
astrocytes in cortex &
basal ganglia.
 Seen in chronic alcoholics
& in Wilson disease.
 C- Toxic Disorders:
 Metals & Industrial chemicals  blindness,
neurotoxicity, diffuse encephalopathy…
 Chronic Alcoholism  cerebellar dysfunction
Acute ethanol  cerebral edema
 Methotrexate white matter demyelination
 Ionizing radiation  white matter ischemia
Types according to etiology:
12345676-
Nutritional & metabolic (DIABETES)
Toxic neuropathies (Drugs)
Vasculopathic (Vasculitis)
Inflammatory (AUTOIMMUNE)
Infectious ( VIRAL, HIV, Leprosy…)
Hereditary neuropathies
Accompanying neoplastic processes
Miscellaneous neuropathies
GENERAL Reactions
 NERVE:
 AXONAL DEGENERATION
DEMYELINATION (segmental)
 Acute
or Chronic
NERVE REGENERATION
REINNERVATION
Types of lesions:
1- Wallerian Degeneration:
Trauma & ischemia
 Axonal & myelin sheath degeneration
distal to transection leading to:




Myelin disintegration
Phagocytosis
Axonal & Schwann cell regeneration
Remyelination
2- Distal axonal degeneration:
Nutritional deficiency & toxic causes 
Metabolic distrubance within axon
Peripheral distal symmetrical degeneration
 Dying back of cell body- Chromatolysis
 Dying back of axon with demyelination
 Regeneration of schwann cells, but limited

3- Segmental demyelination
Axon intact but myelin sheath is
broken → bare axon → ± myelination
→ ‘onion bulb’
* Leukodystrophies, hereditary, metabolic
diseases..
*Inflammatory may follow some viral
infections, mycoplasma, allergic….etc
e.g. Guillain - Barre Syndrome
Toxic/Metabolic Neuropathy
 Diabetes Mellitus
 Vitamin Deficiencies (many Bs, E)
 Heavy Metals, Pb, As, etc.
 Organic Compounds
 CHEMO & Paraneoplastic syndromes
Demyelination/ischemia AND a direct TOXIC
effect to peripheral nerves are seen in
diabetes, which is the MOST COMMON cause
of neuropathy
Traumatic Neuropathy:
 Laceration regeneration rate = 1mm/day
or 1 in/mo.
 Carpal Tunnel Syndrome
 Traumatic (amputation) “Neuroma”
 Morton “Neuroma”
TRAUMATIC NEUROMA
“Regenerating Axons and Schwann Cells, but
with no direction”
MORTON NEUROMA
 Most occur in the 3rd common digital branch of
MEDIAL plantar nerve, i.e., 3rd & 4th toe at distal
metatarsal level.
 Traumatic compression, F ≥ M, Interdigital,
Intermetatarsal
Guillain-Barre Syndrome
 An acute, frequently severe, fulminant
polyneuropathy that is autoimmune in
nature
 Acute inflammatory demyelinating
polyneuropathy (AIDP) is the most
common type of GBS
 M=F
 Adults > children
 75% of cases preceded 1-3 weeks by a
respiratory or gastrointestinal infection
Clinical Presentation
 Motor paralysis +/- sensory disturbances
 Ascending paralysis – “rubbery legs”
 Weakness evolves over hours to days
 Parasthesia of extremities
 Legs > arms
 Autonomic involvement common in
severe cases
 Bladder dysfunction, loss of vasomotor
control
Pathology:
 Segmental demylinization
 Findings include infiltration of nerve by
lymphocytes & macrophages
 CSF:
 ↑Protein (100-1000 mg/L)
 Occasionally transient ↑WCC (10-100/µL)
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