1. Dr. Mohammed Alorjani. MD EBP
NS II 2016
Pathology III
Dr. Mohammed Alorjani. MD EBP 1 1

2. 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

3. 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

4. Gross and microscopic findings
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

5. - Concentric eosinophilic inclusions in the
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.

6. Normal

7. LEWY BODIES

8. 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...

9. 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

10. 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.

11. 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

12. 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

13. 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

14. 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

15. Lou Gehrig
Diagnosed ALS /1939

16. 1942 – alive in 2015

17. 2015 British Academy Film Awards ceremony at The Royal Opera House in London.

18. Pathology: 1- Ant. horn cells of spinal cord 2- Brain stem nuclei
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

21. Acquired Metabolic & Toxic Disorders

22. A- Nutritional Diseases:
1- Thiamine deficiency:
Beriberi & alcoholism
Pathology: Wernicke encephalopathy
hemorrhage in mamillary bodies
hemosiderin deposition
gliosis
Symptoms
Memory loss
Peripheral neuropathy

24. 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

25. 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

26. 3- Liver disease:
Metabolic dysfunction of astrocytes → inability to detoxify accumulated
ammonia → Hepatic Encephalopathy and ‘Flapping tremor’

27. Glial response with formation of
Pathology :
Glial response with formation of
Alzheimer type II astrocytes in cortex & basal ganglia.
Seen in chronic alcoholics & in Wilson disease.

29. Metals & Industrial chemicals  blindness,
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

30. PERIPHERAL NEUROPATHIES

31. Types according to etiology: 1- Nutritional & metabolic (DIABETES) 2- Toxic neuropathies (Drugs) 3- Vasculopathic (Vasculitis) 4- Inflammatory (AUTOIMMUNE) 5- Infectious ( VIRAL, HIV, Leprosy…) 6- Hereditary neuropathies 7- Accompanying neoplastic processes 6- Miscellaneous neuropathies

32. GENERAL Reactions NERVE: AXONAL DEGENERATION DEMYELINATION (segmental)
Acute or Chronic
NERVE REGENERATION
REINNERVATION

33. 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

34. 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

35. 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

39. Toxic/Metabolic Neuropathy
Diabetes Mellitus
Vitamin Deficiencies (many Bs, E)
Heavy Metals, Pb, As, etc.
Organic Compounds
CHEMO & Paraneoplastic syndromes

40. Demyelination/ischemia AND a direct TOXIC effect to peripheral nerves are seen in diabetes, which is the MOST COMMON cause of neuropathy

41. Traumatic Neuropathy:
Laceration regeneration rate = 1mm/day or 1 in/mo.
Carpal Tunnel Syndrome
Traumatic (amputation) “Neuroma”
Morton “Neuroma”
Do you think the word “neuroma” is in quotes because it is NOT a true clonal proliferative neoplasm? Ans: YES

42. TRAUMATIC NEUROMA “Regenerating Axons and Schwann Cells, but with no direction”

43. 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

44. 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

45. 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

46. Pathology: Segmental demylinization
Findings include infiltration of nerve by
lymphocytes & macrophages
CSF:
↑Protein ( mg/L)
Occasionally transient ↑WCC (10-100/µL)

48. THANK YOU