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Diseases of the Nervous System

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Systemic Lupus Erythematosus

• Autoimmune disease that can effect nearly every system• More common in women than men• Symptoms can be vague

– Butterfly rash, sun sensitivity, arthritis, serositis (inflammation of lining of lung or heart), kidney disorder, neurologic disorder

– Occurs in “flares”• Organ threatening (decrease lifespan) vs non-organ

threatening (normal lifespan)– top causes of death: kidney disease, infections, CNS lupus,

blood clots, cardiovascular complication• Treatments

– Antimalarial drugs and corticosteroids (anti-inflammatory)– Chemotherapeutic agents (immunosuppressant and inhibit cell

proliferation)

3

Depression

• Low levels of norepinephrine and serotonin in the CNS

• Patients’ brains often up-regulate NT receptors in response to low levels of NT

• Treatments– Monoamine oxidase inhibitors (MAOI)= higher levels

of NT in the synaptic cleft or block NT reuptake by presynaptic neuron; cause high bp

– Selective serotonin reuptake inhibitors (SSRI)= inhibit reuptake of serotonin by the presynaptic neuron; less side effects than MAOIs

4

Bipolar disorder

• Periods of depression followed by periods of euphoria

• Usually strikes young (~20 yrs old) and episodes recur throughout life

• Treatments– Lithium= stabilizes levels of monoamines– Antidepressants for depressive attacks and

antipsychotics for psychotic attacks– Anticonvulsants= control sensitivity of neural

membranes to stimulatory signals

5

Schizophrenia

• Disorganized thinking and speech, delusions, hallucinations

• Onset usually between 25-35

• Excess neurotransmission by dopamine-producting neurons

• Treatments – Drugs that inhibit dopaminergic

neurotransmission

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Parkinson’s disease

• Loss of dopamine-producing neurons in a specific region of the basal ganglia– Interferes with initiation of movement

• Link between this disease and people who are known for their “straight arrow” personality

• Treatments– L-dopa= precursor to dopamine that crosses BBB;

side effect is schizophrenia-like behavior– Dopamine agonists= bind to and activate dopamine

receptors; side effect is triggering thrill-seeking behaviors

7

Curare poisoning

• Antagonist for Ach receptors (non-depolarizing)– Blocks muscle contraction– Does not cross BBB

• Death from respiratory muscle failure• Treatments

– Neostigmine= drug that inhibits acetylcholinesterase so that more Ach competes for receptor binding

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Myasthenia gravis

• Autoimmune disease; B cells make antibodies that bind to and block Ach receptors of the neuromuscular junction

• Neuromuscular disorder characterized by progressive muscular weakness and, if untreated, respiratory muscle failure

• Treatments– Mechanical ventilation– Neostigmine and related drugs– Thymectomy (removal of the thymus); thymus is

involved in tolerance and thymic abnormality is associated with this disease

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Multiple sclerosis• Appears to be an autoimmune disease characterized by

demyelination of neurons in CNS• Symptoms include blurred or double vision, muscle

weakness, loss of balance, spasticity, muscle fatigue, mild cognitive impairments

• Patterns: relapsing-remitting, primary progressive, or benign

• Rarely fatal• ~twice as common in women than men, but men have

more rapidly progressing disease• ~twice as common in people of European ancestry• Treatments

– Anti-inflammatory agents such as corticosteroids– Interferon beta slows progression

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Amyotrophic Lateral Sclerosis• Loss of motor neurons, both lower and upper• Pathogenesis not well understood, but may involve

glutamate toxicity– ↑glutamate prolonged opening of Ca2+ channels Ca2+

activated proteases cellular damage• Symptoms include muscle weakness and cramping,

muscle atrophy, loss of muscle control involved in respiration, inability to coordinate swallowing

• Patterns: lower motor neurons first= asymmetric weakening of one of the limbs, upper motor neurons first= difficulty moving face and tongue

• Most patients die within ~5 yrs• More common in men than women• Treatments

– Riluzole= inhibits release of glutamate from presynaptic neurons– Baclofen= muscle relaxant that relieves muscle spasticity

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Peripheral neuropathy

• Death of peripheral nerves• Can occur as a result of a number of

disorders (renal failure, alcoholism, diabetes, vitamin B12 deficiency, lead poisoning, lupus)

• Symptoms: – sensory= loss of sensation in extremities– motor= weakness of skeletal muscles– autonomic= orthostatic hypotension and

impaired GI function, thermoregulation, vision, & sexual function

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Guillain-Barre syndrome

• Autoimmune attack on myelin in peripheral nerves (as opposed to MS)

• Often occurs after viral infection, sudden disease onset

• Many cases are mild, but some require mechanical ventilation

• ~1/2 of patients fully recover within 1 year

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Spinal cord injuries

• Death of nerve cells generally leads to permanent loss of function

• Trauma or glutamate exotoxicity can cause cell death of neurons

• Degree of disability is related to region of spinal cord injury

• Injury of cervical nerves= quadriplegia• Injury of thoracic nerves= paraplegia• Injury to lumbar or sacral region= some loss of sensation

and motor control in legs and hips• Treatments

– Relief of compression (by traction or surgery)– Methylprednisone= corticosteriod that stabilizes cell membranes

and reduces inflammation, within 8 hrs of injury

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Autonomic dysreflexia

• Abnormal activation of the sympathetic nervous system

• Major concern for people with spinal cord injuries

• Triggered by painful or irritating stimuli (full bladder, UTI, pressure wounds, GI conditions, menstrual cramps, labor & delivery)

• Nerve signals get blocked at injury and do not reach brain triggers reflexes in SNS

• Most dangerous effect is sudden vasoconstriction sharp rise in bp seizure, stroke, or death

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Organophosphates

• Active ingredient in nerve gas and many pesticides

• Inhibit acetylcholinesterase• Effect on autonomic function:

– ↑ parasympathetic system ↑ GI function, ↑ respiratory secretions, ↓ HR

• Effect on muscle:– Depolarizing paralysis of skeletal muscle

• Effect on CNS:– Triggers convulsions

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Botulinum toxin

• Comes from bacteria • Most toxic substance known to man• Cleaves docking proteins off of Ach-containing

vesicles prevents release of Ach at neuromuscular junction and in autonomic NS

• Symptoms: dry mouth, double vision, symmetric flaccid paralysis, difficulty swallowing & speaking, paralysis of respiratory muscles

• Treatments– Respirator for several weeks

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Strychnine poisoning

• Antagonist to glycine receptors (glycine is an inhibitory NT that acts on lower motor neurons)

• Lower motor neurons fire inappropriately muscle spasms throughout body severe pain

• Treatments– Valium= controls muscle spasms

• Must be monitored for rhadomyolysis – release of toxic levels of myoglobin from

damaged muscle cells nephrotoxic

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Stroke• Ischemic stroke= portion of the blood flow to the brain is

blocked– Occurs when thrombus or embolus obstructs blood flow– ~ 85% of strokes

• Intracranial hemorrhage= rupture of blood vessel in brain– Often result from congenital anatomical abnormalities, ~25% are

fatal– ~15% of strokes

• Mechanism of cell death: ↓glucose & oxygen ↓ATP loss of ion gradients anoxic depolarization release of high levels of glutamate

• Treatments– Ischemic strokes treated with thrombolytic drugs= break down

blood clots; administer within 3 hrs– Hemorrhagic strokes treated with surgery or clotting agents– Drugs to block glutamate and its toxic effects

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Diseases of the Endocrine System

20From class notes 10/23/06 (S.Shore)

hypothalamus

thyroid

anterior pituitary

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Iodine deficiency

• Non-toxic goiter• Leading cause of brain damage worldwide, even mild

cases reduce IQ• Esp. problematic for pregnant women due to

requirements of the fetus• Universal Salt Iodization adopted by WHO in 1993• Diagnosis: goiter, increased TSH levels• Mechanism: ↓ iodine inability of thyroid to make T3/T4

↓ serum T3/T4 less T3/T4 inhibition of anterior pituitary TSH synthesis & less inhibition of hypothalamus to turn off TRH ↑ serum TSH & ↑ serum TRH ↑ thyroid growth (goiter) increased efficiency of T3/T4 production

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Hyperthyroidism

• Excessive thyroid hormone• Ex: Grave’s disease= autoimmune disease

– Auto-antibodies stimulate TSH receptor independent of TSH

– ↑ T3/T4 negatively feeds back on anterior pituitary to ↓ TSH & on hypothalamus to ↓ TRH

– Symptoms: hypermetabolism, increased sympathetic activity (T3/T4 increase expression of -adrenergic receptors), psychological effects, overactivity of muscles retracting eyelids

– Treatments: • Surgery to destroy thyroid gland (need to replace T3/T4)• Drugs to block T3/T4 synthesis• Lithium= inhibits T3/T4 secretion

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Hypothyroidism

• Primarily due to destruction of thyroid gland– Ex: Hasimoto’s thyroiditis= autoimmune destruction,

blocks TSH receptor (as opposed to Grave’s disease that stimulates receptor)

• Secondarily due to deficiency of TSH– Symptoms: vary with age at onset

• Juvenile/adult: hypothermia, fatigue, decreased cardiac output, intellectual slowness, decrease sweating, weight gain, edema, etc.

• Childhood: cretinism (severe mental and growth retardation)

• Treatments– Administration of T3/T4

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hypothalamus

Anterior pituitary

Liver and other cells

GHRH

GH

IGF-1

-

-

exercisestress

fastinglow plasma glucose

sleep+

+SS

-

-

From class notes 10/23/06 (S.Shore)

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Acromegaly

• Caused by increased growth hormone secretion– Tumor of anterior pituitary that secretes GH

• Oral glucose challenge: large dose of glucose normally shuts off GH secretion, but not in acromegaly

– Hypothalamic abnormality that ↑ GH secretion– Extrapituitary neoplasm that secretes GHRH

• Symptoms: ↑ bone (wider) & muscle & connective tissue growth, enlargement of hands and feet, facial feature changes (coarsens features), ↑ diabetes, ↑ heart mass congestive heart failure

• Treatments– Surgery to remove tumor– Analogue of somatostatin (negative regulator of GH secretion by

anterior pituitary)– GH receptor antagonist

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Gigantism

• Etiologically identical to acromegaly

• Occurs before epiphiseal plates close, allowing long bone growth in addition to wide bone growth

• Results in excessive height

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Dwarfism

• Proportionately reduced size and stature• Caused by insufficient GH secretion or

action• Treatments

– Administration of human recombinant GH

• Achondroplasia: genetic disease caused by mutation in FGF (fibroblast growth factor) receptor– Disproportionate: small stature & limbs with

enlarged head size

28From: Pathophysiology of Disease, McPhee et al. Appleton and Lange, Norwalk, CT

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Diabetes Mellitus (Types I & II)Type 1 Type 2

Synonym IDDM NIDDM

Onset Age < 30 years >40 years*

Body weight not obese obese (>80%)

Prevalence 0.2 - 0.3% 6-10%

Racial differences higher in person of Northern European descent

higher in persons of African descent and in native Americans

Genetics: Twin studies 30-50% concordance rate 90-100% concordance rate

Treatment with insulin always necessary not usually necessary

insulin secretion severe deficiency variable: hyperinsulinemia sometimes present

insulin resistance rare usual - due to receptor and/or postreceptor defects

circulating islet cell antibodies (sometimes antibodies to insulin as well)

yes no

ketosis common rare

associated with other autoimmune phenomena

Yes No

From class notes on October 30, 2006 (S.Shore)

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Pathogenesis of Type I

• Autoimmune destruction of -cells of pancreas

• May be triggered by viral infection

• Genetic component= linked to MHC II genes

• Onset is usually during adolescence

• Effect is not observed until >70% of -cells are lost

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Pathogenesis of Type II

• Due primarily to insulin resistance

• Initially leads to increase insulin secretion, but eventually -cells can deplete and cause reduced insulin secretion

• Obesity and chronic inflammation may contribute to insulin resistance

• Strong genetic tendency

• Strong correlation with obesity

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Acute Complications of Types I & II1. Hyperglycemia

• Loss of glucose in urine loss of water hypotension• Increased plasma osmolarity water leaves the tissues

coma (if severe)• Ketosis= lack of insulin ↑ lypolysis ↑ ketone synthesis

↓ plasma pH (more acidic) metabolic complications• Especially bad for brain!

• Hyperkalemia= ↑ plasma K+ due to lack of insulin and increased plasma glucose changes in cell membrane potential (depolarizing) cardiac arrhythmias

• Treatment: replacement of water, electrolytes, and insulin injections

2. Hypoglycemia (arising from insulin overdose)• Sympathetic discharge= low glucose stimulates hypothalamus

sweating, shaking, anxiety, palpitations, weakness, tremor, tachycardia

• Neuroglycopenic symptoms= lack of glucose to brain confusion, irritability, headaches, weakness, abnormal behavior, lack of motor coordination, convulsion, coma

• Treatment: oral or IV glucose, glucagon injection

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Chronic Complications of Types I & II1. Microvascular disease (caused by ↑ glycosylation of

proteins or ↑ sorbitol production)• Retinopathy= blindness• Nephropathy= renal disease, requires dialysis and/or kidney

transplant

2. Macrovascular disease (most common in type II)• Coronary artery disease• Cerebrovascular disease• Peripheral vascular disease (leading cause of death for type II

diabetics)

3. Neuropathies (peripheral and autonomic, caused by demyelination and loss of nerve fibers)

• Loss of sensation, tingling & numbness in extremities, autonomic problems (tachycardia, impotence, incontinence, GI problems)

4. Foot ulcers (caused by sensory neuropathy, infection, vascular disease)

5. Infections (caused by effects of ↑ glucose on neutrophil function, skin eruptions, vascular disease, ↑ plasma glucose)

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Treatment of Types I & II

• Type I– Insulin injections

• Type II– Diet– Exercise– Glucophage= ↑ insulin sensitivity, ↓ glucose

production– Sulfonylureas= ↑ insulin release– Insulin= in severe cases when insulin secretion is

depressed– Thiazolindiones= PPAR agonists that ↓insulin

resistance