Download E1 Lec 16 Peripheral Neuropathy

OS 211 [A]: Integration, Coordination, and Behavior
Lec 34: Peripheral Neuropathy
December 6, 2013
Geraldine S. Espritu, MD
TOPIC OUTLINE
I. Overview
II. Peripheral Nerve Damages
III. Basic Physiology
IV. Examination
V. Generalized/Polyneuropathy
VI. Focal Neuropathy
VII. Others
1
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Will take years to get to the degeneration stage
If nerve has a demyelinating problem (sheath loss stage), it is
usually reversible because the neuron is still intact, but once
disconnection occurs, damage is permanent
Legends:
From the Powerpoint presentation and 2016
From the lecture 2016A
From our lecture
Hello guys! Ma’am said to focus on table 6 and table 7 (pages 5 and 6) for her
5 questions. Her favorite questions are still the same as in 2016A’s exam (in
boxes), so we just added a few more notes from her very short lecture.
I. OVERVIEW
A. PERIPHERAL NERVES
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For your nerve to function, everything needs to be healthy: neuron,
myelin and axon
Myelinated
by
individual
Schwann
cells
(instead
of
oligodendrocytes in the CNS which are myelinated like an octopus)
1:1 ratio of peripheral nerve to Schwann cell
Damage confined to neuron, axon and myelin
Figure 2. Typical Process of Damage in Peripheral Nerves.
NEURONAL/NEUROPATHY
 Best way to kill a nerve is to cut its axon (neuron), faster than to
demyelinate it
 Most common problem: if anterior horn or dorsal root is attacked
(eg. Herpes Zoster)
 In a war, you want to preserve the headquarters, the headquarters
is the dorsal root
 Attack the headquarters to destroy the government
 If you attack the myelin only, you only hit the satellite stations
Figure 1. The Peripheral Nerve
BASIC PRINCIPLES
 Functional Classification of a Nerve:
o Motor
o Sensory
o Autonomic
 Normal nerve integrity and function rely on the proper functioning of
the four components:
o Neuron
o Axon
o Myelin
o Connective Tissue – there are a lot of diseases that affect the
connective tissue or vascularization of the nerve that would
cause damage (ex. Diabeties, ischemia, drugs, alcohol)
 Interruption or impairment of any of these structures can lead to
transient or permanent nerve injury.
 Symptoms parallel function: motor, sensory, autonomic
 Also can be affected by problems of supply (glucose, protein)
PERIPHERAL NERVE DAMAGE
 Pathology:
o Axonal
o Demyelinating
o Combined
II. PERIPHERAL NERVE DAMAGES
A. TYPICAL DAMAGE PROCESS

Starts with demyelination, then compression, then disconnection
(here damage is permanent) and then degeneration (retrograde
damage, takes years)
SEAN, MISH, KYLE
Figure 3. Neuropathy on Dorsal Root Ganglion.
Table 1. Neuronal vs. Axonal Degeneration.
Description
Classification and
Prognosis
Examples
Neuronal Degeneration
Primary
Inherited disorders: e.g.
Degenerative
loss/destruction of
spinal muscular
disorder of neuron
cell body with no
nerve cell bodies
atrophies, amyloidosis
possibility of
accompanied by
Motor Neuron Disease
recovery
degeneration of
their peripheral and
Toxic: cadmium
central axons
poisoning
Polio virus
Breakdown of the
axon and myelin
sheath that
progresses toward
the nerve body
Axonal Degeneration
Axonal polyneuropathies
Recovery is
delayed and often
incomplete
Most toxic/metabolic
neuropathies
POLIO
 A lot of people have polio-like symptoms now
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Lec 34: Peripheral Neuropathy
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Polio is acute, acquired in childhood
One limb is shorter than the other
Anterior (L3) horn cells are destroyed
Once neuron is targeted, there’s no way of recovery. Once you
grow up with polio, damage doesn’t go away
ALS (not mentioned by Ma’am)
 Motor neuron disease
 Degenerative disease with slow muscle atrophy. All motor neurons
affected, not just one limb (versus polio).
improper
manufacture
(congenital) of
myelin sheaths
with relative
sparing of axons
Syndrome
Hereditatry disorders of
Schwann cell-myelin
metabolism:
e.g. metachromatic
leukodsytrophy, DejerineSottas disease
III. BASIC PHYSIOLOGY
OS 213
In acquired disorders,
recovery is dependent
on remyelination or
demyelinated
segments, which can
take from days to
several months
A. MYELIN
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Myelin is a good insulator and facilitates conduction
The thicker the myelin, the faster the nerve conduction
Myelinated nerve is 50x faster
Myelin also serves as a protector
Compression or
entrapment
mononeuropathies; CTS
B. PERIPHERAL NEUROPATHY
1. Variety of syndromes that result from lesions of the peripheral
nerve
o Cranial nerve (except I and II)
 Smelling and vision; they are not peripheral nerves because
they are outpouchings of the cortex.
o Spinal nerve (motor, sensory, autonomic)
2. Mononeuropathy (single)
3. Mononeuropathy multiplex (multiple)
4. Generalized/polyneuropathy
Figure 4. Myelinated nerves. (Left) Healthy nerves surrounded by
myelin, (right) myelinated nerve in high resolution.
PHYSIOLOGICAL EFFECTS OF DEMYELINATION
 Impede salutatory conduction
 Temporary inductions by heat and exercise, hyperventilation,
smoking, fatigue
 If with myelin: like the LRT which only stops at some points, faster
 If without myelin: like a jeepney which stops everywhere, slower
 Worst case if everything is demyelinated
 Surrounding Schwann cells can be generous and give myelin
sheath to the demyelinated axon
 Recovery is good in demyelination
2016A: Favorite question!
1. All are peripheral nerves except I and II. All spinal nerves are
considered part of peripheral nerves. CN I and II do not have Lower
Motor Neurons.
HISTORY
 Determine whether presenting symptom is sensory, motor,
autonomic
 Evolution, order of body parts involved (symmetrical vs.
asymmetrical)
 Onset, duration, temporal course (acute, sub acute,
progressive, relapsing or remitting) – the most important
questions to ask
o 2016A: Onset important. Classify the disease based on how
fast the damage is: if fast, axonal; if slower, demyelinating
 Exposure to toxin, concurrent medical history, family history,
medications, injury, prior infection, dietary habits
o Ex. Silver tooth filling or gold teeth can cause dementia
because of prolonged exposure. Choose the white pasta for
your teeth!
SENSORY SYMPTOMS
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Sensory involvement is an important diagnostic key
This is usually the only reason why they go to the doctor
For peripheral nerves, important to remember your dermatomes!
SYMPTOMS OF NEUROPATHY
Fig. 5. Conduction in Myelinated and Demyelinated Fibers.
Myelinated nerve fibers (top) conduct faster while demyelinated nerve
fibers (bottom) conduct more slowly.
SEGMENTAL DEMYELINATION
Table 2. Segmental Demyelination. Know the classification and
examples.
Description
Classification and
Prognosis
Examples
Breakdown
Immune-mediated
acquired demyelinating
neuropathies:
Acquired or
e.g. Guillian-Barré
SEAN, MISH, KYLE
Recovery does not
occur in congenital
disorders
Table 3. Symptoms Of Neuropathy. A positive symptom is an
abnormal or exaggerated feeling of something that isn’t felt normally,
whereas a negative symptom is not feeling the stimulus that is being
given to you.
System
Positive
Negative
Cramps
Weakness
Motor
Fasciculations
Fatigability
Myokynesia (quivering)
Hypotonia
Restless legs
Arreflexia
Tightness
Deformities (pes cavus, claw
hand)
*especially if hitting a motor
nerve
Parasthesias
Loss of vibration sense
Sensory
Tingling
Loss of joint position sense
(large fiber)
Arreflexia
Sensory ataxia (positive
Romberg test)
Hypotonia
Sensory
Burning, jabbing pain
Loss of pain sense
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Lec 34: Peripheral Neuropathy
(small fiber)
Autonomic
(dysesthesias)
Hyperhidrosis
(excessive sweating)
Excess saliva
Loss of temperature sense
Orthostasis
Erectile dysfunction
Bowel and/or bladder
dysfunction
Anhidrosis
NOTE: Treatment of hyperhidrosis is botox. It is a neuromuscular
junction blocker, but it has no connection to the autonomic functions.
Even neurologists are still baffled as to why botox works for
hyperhidrosis.
Table 4. Sensory Symptoms.
Positive
Burning
Pricking pain
Electric, shock-like feelings
Tightness
Hypersensitivity to touch
Negative
Numbness
Deadness
Feeling of wearing gloves or
walking on stilts
Loss of balance
Painless injuries
OS 213
1. Motor System Evaluation
 Gait
 Reflexes
 Abnormal movements
 Tone
 Strength
2. Sensory Testing
 Testing position
 Palpate for pulse
 Testing with pinprick
 Testing with cotton wool
 Testing with a tuning fork
3. Approach
 Compare distal sensation to proximal sensation
 Look for symmetry by comparing one side to the other
 Test each of the dermatomes
TEST FOR NEUROPATHY
1. Monofilament Screening Test
2. Nerve conduction velocity measurements
3. Testing for reflex - can give one an idea if there is a disruption in
the reflex arc
IV. EXAMINATION
A. COMPLETE PHYSICAL EXAM
NOTE: TAKE GOOD HISTORY
*Look and Locate: Compare right and left, memorize dermatomes
 Systemic disorders
o Diabetes
o Vasculatis
o Lupus
 Orthostatic hypotension
 Atrophy, Swelling Skin changes, Mees’ lines
o Look for rashes
Figure 7. Tests for Neuropathy.
V. GENERALIZED/POLYNEUROPATHY
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A. Herpes Zoster
B. SLE
Classic picture of advanced, diffuse neuropathy with distal wasting,
weakness, absent tendon reflex, & glove & stocking distribution
Distal nerves are affected first
Usually sensory fibers are affected first before motor fibers
Something generalized is affecting a lot of your nerves at one time
It involves generalized medical conditions:
o Endocrine
o Toxicologic
 Patients undergoing chemotherapy may exhibit pain and
numbness because of the toxic effects of the medications.
o Nutritional
 Common among those who don’t eat meat or with Vit D
deficiency
o Vasculitis
A. DIABETIC NEUROPATHY
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C. Lupus-like symptoms, can be
rheumatoid arthritis.
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D. Hand atrophy
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Figure 6. Physical Exam. Look
and locate signs of Herpes
Zoster, SLE, Lupus-like
symptoms, atrophy and diabetic
foot. Grandparents’ feet can be
patchy, which can indicate that
circulation is compromised.
E. Diabetic foot: dry skin,
discoloration, poor perfusion to toes
B. NEUROLOGIC EXAM
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Optic pallor
Deep tendon reflex
Pain, light touch, position, vibration sense
Palpate peripheral nerve trunks
Most common, rising
Complications: neuropathy
An estimated 10-65% of patients with diabetes have some form of
peripheral neuropathy.
Neuropathy is estimated to be present in 7.5% of patients at the
diagnosis of diabetes.
If you are a diabetic, wish for a positive neuropathy. Everything will
be heightened, including kisses
50% have distal symmetric polyneuropathy, and 25% have
compression or entrapment neuropathies (mainly carpal tunnel
syndrome). Patients complain of ‘ngalay’ or tingling
Diabetes affects all 4 major components:
o Metabolic changes (sorbitol)
o Microcirculation
o Neuropathy
o Retinopathy
CLASSIFICATION OF DIABETIC NEUROPATHY
1. Diffuse Somatic Neuropathy
 Sensorimotor
 Distal symmetrical sensorimotor polyneuropathy
o Primarily small-fiber neuropathy
o Primarily large-fiber neuropathy
o Mixed
2. Focal Neuropathy – numbness of feet and hands or problems of
nerve roots
 Mononeuropathy (CTS)
 Monnoneuropathy multiplex
 Amyotrophy (nerve roots)
NEUROPATHIC PAIN
SEAN, MISH, KYLE
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Lec 34: Peripheral Neuropathy
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A. Diffused Type
B. Focal Type
C. Focal Type
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Figure 8. Diabetic Neuropathy. Diffused and Focal type
VASCULAR THEORY
1. Endoneurial ischemia develops because of increased endoneurial
vascular resistance to hyperglycemic blood.
2. Various metabolic factors, including formation of advanced
glycosylation end products, also have been implicated.
3. Leading to capillary damage, inhibition of axonal transport, Na+/K+ATPase activity, and finally to axonal degeneration
METABOLIC THEORY
1. Proposes that hyperglycemia causes increased levels of
intracellular glucose in nerves, leading to saturation of the normally
used glycolytic pathway.
2. The extra glucose is shunted into the polyol pathway and converted
to sorbitol and fructose by the enzymes aldose reductase and
sorbitol dehydrogenase.
3. Accumulation of sorbitol and fructose leads to reduced nerve
myoinositol, decreased membrane Na+/K+-ATPase activity,
impaired axonal transport, and structural breakdown of the nerve,
causing slowing of conduction velocities
Figure 9. Pathogenesis Of DM Nephropathy Based On The
Vascular Theory. Did not discuss that much, she discussed the
metabolic theory diagram more. NERVE DIES OUT DUE TO
ISCHEMIA/POOR FLOW TO NERVE
Figure 10. Pathogenesis of DM Neuropathy based on the
Metabolic Theory. Reduced blood flow shuts down pump,
hyperglycemia increases neurovascular resistance, and increased
sorbitol decreases blood flow – also contributing to the damage. This
looks complicated, but just look at the source: exercise and
control of blood sugar.
ASIDE FROM ISCHEMIA, HIGH SUGAR CONTENT CAUSES MORE DAMAGE
BECAUSE OF IMBALANCE (FRUCTOSE, SORBITOL) WHICH ARE IMPORTANT
FOR THE NERVE.
MANAGEMENT OF DM NEUROPATHY
SEAN, MISH, KYLE
OS 213
Primary concern: Control of Blood Sugar (stop whatever is
attacking the nerve)
Ameliorate painful symptoms
Improve neurovascular circulation - decreased circulation (leading
to nerve death) is the main reason why DM patients have
neuropathy
2016A: Usually have foot cut off because patients cannot feel and
has an eroded wound; if more than 70% occlusion, amputate
Wearing wedges can help prevent focal compressions in your legs
Do an ultrasound first before you amputate
B. GUILLAINE-BARRE SYNDROME
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Autoimmune response triggered via infection or vaccination
o Immune cells attack Schwann cells leading to demyelination
o Mediated by antibodies (but also CMI)
Background: Classic Guillaine-Barré syndrome (GBS) is an acute,
ascending, and progressive neuropathy characterized by
weakness, paresthesias, and hyporeflexia.
You get an infection through vaccination, colds or cough. After two
weeks, walking feels heavy, then eventually becomes paralyzed.
In severe cases, muscle weakness may lead to respiratory failure.
Severe labile autonomic dysfunction may also occur.
Maximal weakness typically occurs 2 weeks after the initial onset of
symptoms but may evolve early and abruptly.
Begins as numbness
Attacks the virus, then your own nerve
EPIDEMIOLOGY AND ECONOMIC IMPACT
 Most common acute neuropathy in clinical practice.
 GBS affects between 1-4 per 100,000 of the world’s population
annually.
 Sex: predominant in males 1.5:1 (sees a lot of females now
together with males)
 Age: all ages
o Bimodal distribution
o Peaks at 15-35 and 50-75 years old
 The costs in the US have been estimated as $110,000 for direct
health care and $360,000 in lost productivity per patient.
AUTOIMMUNE THEORY
 Impede salutatory conduction
 Targets the Schwann cells
 GBS is believed to result from an autoimmune response triggered
by an antecedent illness or by any of a long list of medical
conditions.
 Usually when patient clears out a vaccine or has an infection,
immune cells attack Schwann cells leading to demyelination
 The autoimmune response seems to have both humoral and cellmediated components.
 Recognized variants: AIDP, AMAN (Acute Motor Axonal), MFS,
AMSAN (Acute Motor Sensory Axonal)
 AIDP: humoral immune reaction to schwann cell membrane or
myelin
 AMAN and MFS are strongly associated with non protein anti
ganglioside antibodies (antiGQ1b antibodies for MFS and anti
GD1a anti GM1 for AMAN)
 Common pathology is loss of myelin due to antibody attack on
schwann cell and myelin sheath.
 In a subset of patients with GBS, axonal damage results from a
direct cellular immune attack on the axon itself.
 Segmental pattern
Figure 11. Segmental Demyelination and Remyelination: Sural
Nerve Biopsy. This is the common pathology in GBS. The
internodal segment (arrow) shows marked reduction of myelin
thickness compared to the adjacent internodes, indicating remyelination
of a focally demyelinated axon. JUST TARGETS THE SCHWANN
CELL, JUST A NODE NOT THE WHOLE NERVE Teased nerve fiber
preparation.
CAUSES
 2/3 of patients have a history of GI or respiratory infection from 1-3
weeks prior to onset of weakness.
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Lec 34: Peripheral Neuropathy
Table 5. Causes of GBS
Infections
Chlamydia
Campylobacter jejuni
Hepatitis B
Mycoplasma pneumonia
Cytomegalovirus
Epstein-Barr virus
Human Immunodeficiency Virus
(HIV)
Vaccinations
Group A streptococci
Rabies
Swine flu
Influenza
*When you get a vaccine, make
sure you don’t have other
infections (cough, cold, UTI)
because you might develop an
immune response and have
GBS.
FEATURES OF GBS
 Onset Weakness:
o Most often symptomatic in legs
o Pain: Low back & legs
o Paresthesias: Distal
 Weakness
o Starts as distal, ascending weakness
o Distribution: Proximal + Distal; Symmetric
o Severity: Quadriplegia in 30%; Bedbound another 30%
o Respiratory failure
 Cranial Nerves (70%)
o VII (FACIAL DIPLEGIA)
 Extra-ocular: Miller-Fisher (atypical, frozen eyeball)
 Tongue: Symmetric; Common (50%)
 Sensory: Paresthesias: Initial symptom in 50%
o Eventually occur in 70% to 90%
o Pain Prominent in 70%
PROGNOSIS AND TREATMENT
 GBS is a monophasic disease, symptoms start to resolve or
plateau by the 4th week of illness; once you get the cells out of the
body, symptoms will go away
 Watch out for respiratory failure
 Weakness usually resolves with supportive care but best if with
treatment (IVIG agent binds with IVIG then flush out or plasma
exchange remove the offending agent)
o
Remove the offending agent
SUPPORTIVE CARE
 Most important in the treatment of GBS is excellent general care
and intensive care
 Respiratory support
o 2016A: Respiratory failure is the most common cause of death
 Fluids and nutritional support
 Monitoring and good nursing care
2016A Questions:
2. What differentiates DM from GBS? Acute (GBS) vs. Chronic (DM).
Sensory (DM) vs. Motor (GBS). GBS leads to death because of
respiration failure (paralyzed muscles of breathing), DM spares trunk
muscles.
3. What is the most common pathology of GBS? Mostly
demyelinating, sometimes attacks axon first.
DIAGNOSTIC STUDIES
 Diagnosis usually is made on clinical grounds and confirmed by
tests
 Lumbar puncture and spinal fluid analysis
o Why do a lumbar puncture? Because myelin is protein. The
protein disintegrates and can sometimes be found in the CSF.
 Most, but not all, patients have an elevated level of CSF protein
(>400 mg/L), with no elevation in CSF cell counts
 “Protein cell dissociation”
 High protein because myelin is punctured, thus high myelin
OS 213
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
Wrist drop = radial nerve
Trigeminal neuralgia – from chin then goes all the way up (video)

When the whole side of the face is paralyzed, the lesion is
peripheral (Bell’s Palsy)
When the forehead is spared, the lesion is central (e.g. Stroke)
B. FACIAL NERVE

Figure 11. Left: Areas of possible nerve damage. Right: Bell’s
Palsy
VII. OTHERS
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Acute vs. Chronic
Starts as focal but become generalized
o Hansen’s disease (leprosy): increase due to lack in funding of
medication
o Lead
o Mercury
o Diabetes
o CTD (Connective Tissue)
Mixed sensory and motor
Mixed axonal and demyelinating
o Autoimmune
o Paraneoplastic
o Toxicologic/chemotherapy
2016A Questions:
4. The following should cause mixed axonal and demyelinating
neuropathy except… Autoimmune paraneoplastic,
toxicologic/chemotherapy cause it, rule out these.
Table 6. Etiology. May get 2 questions from here. As a doctor, you
should know the etiology so you can manage appropriately.
Structure
Disease
Anterior Horn Cell
Poliomyelitis
Dorsal Root Ganglia
Herpes Zoster
Myelin Sheath
Guillain Barre
Axons
Arsenic
Myelin and Axon
Alcohol/Nutritional
Blood Vessels
Diabetes
Connective Tissue
SLE, Amyloid
 Cheap hair dye with chemicals can cause frequent headaches
 Plastic or paint of toys may also contain toxic chemicals
VI. FOCAL NEUROPATHY
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Involves only one nerve. Unlike polyneuropathy, the symptoms of
focal neuropathy are specific for the nerve injured or affected.
Commonly in the hand, leg or lower back.
Any nerve can be affected
Often due to compression = demyelinating
Trauma = both axonal and demyelinating
Example: carpal tunnel syndrome
Trigeminal neuralgia = “kumakapal, sumasakit”
A. NEURALGIA
SEAN, MISH, KYLE
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Lec 34: Peripheral Neuropathy
Figure 12. Normal sural nerve biopsy. Normal density of myelinated
nerve fibers. One micron thick toluidine blue-stained plastic-embedded
cross section. All the nerves should be round and healthy with good
blood flow. Myelin has good supporting tissue. MARAMING MALIIT NA
MYELIN FIBERS
Leprosy
Diphtheria
METABOLIC/ENDOCRINE
Renal/Hepatic Failure
Hypothyroidism
TOXIC
Lead
Arsenic
DRUG INDUCED: INH
OS 213
Sensory
Motor
Sensory/sensorimotor
Sensory/sensorimotor
Motor
Sensory
Sensory
VII. SUMMARY
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First: Determine if patient has peripheral neuropathy
Second: Determine pattern of peripheral neuropathy involvement
Third: Determine the underlying cause
Treat/Correct cause as well as the symptoms
END OF TRANSCRIPTION
Appendix. Posterior and Anterior Dermatomes
Figure 13. Amyloid neuropathy: sural nerve biopsy. Amyloid
deposits (arrows) in the endoneurium, in a patient with amyloid
neuropathy caused by a transthyretin gene mutation. Congo red stain
paraffin section. Dead Sural nerve shows occlusion with amyloid
deposits. There is no myelin, integrity and supportive tissue. HAS
AMYLOID, NO MORE MYELIN (Common in connective tissue diseases and
amyloid neuropathy)
Figure 14. Lepromatous neuropathy: sural nerve biopsy. Several
Schwann cells contain Mycobacterium leprae bacilli (arrow). Electron
microscopy, original magnification x5500. There is no myelin and the
shape gone, last fiber of whole sural nerve. It attacks everything myelin,
including axon supporting tissue. Leprosy is coming back because the WHO
cut off the funding for their drug.
Table 7. ACQUIRED. More questions from this table.
Disorder
Diabetes
NUTRITIONAL
Vitamin B,
Vitamin E,
Alcoholic
IMMUNE MEDIATED
GBS
CIDP
MNCB
VASCULITIS
PARANEOPLASTIC
Lung CA
Lymphoma
INFECTIOUS
Herpes
SEAN, MISH, KYLE
Presentation
Sensory, sensorimotor, focal,
multifocal
Sensory
Sensorimotor
Acute: motor, sensory, autonomic,
opthalmoparesis
Chronic: motor sensorimotor,
demyelinating
Multifocal motor
Multifocal
Sensory
Motor, Sensorimotor
Sensory radiculopathy
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