NS II 2016 Pathology III Dr Mohammed Alorjani

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 6 th. 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 (Poly. Q) 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 Ø hemorrhage in mamillary bodies hemosiderin deposition Ø gliosis Symptoms Ø Memory loss Ø Peripheral neuropathy Ø

2 - Vitamin B 12 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: Ø Metabolic dysfunction of astrocytes → inability to detoxify accumulated ammonia → Hepatic Encephalopathy and ‘Flapping tremor’

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

C- Toxic Disorders: Ø Metals & Industrial chemicals blindness, neurotoxicity, diffuse encephalopathy… Ø Chronic Alcoholism cerebellar dysfunction Acute ethanol cerebral edema Ø Methotrexate white matter demyelination Ø Ionizing radiation white matter ischemia

PERIPHERAL NEUROPATHIES

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

GENERAL Reactions NERVE: Ø AXONAL DEGENERATION ØDEMYELINATION (segmental) Ø Acute or Chronic ØNERVE REGENERATION ØREINNERVATION

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 = 1 mm/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 3 rd common digital branch of MEDIAL plantar nerve, i. e. , 3 rd & 4 th 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)

THANK YOU