Peripheral nervous system
pathology
General informations about anatomy, physyology and pathology of
the peripheral nervous system
Polineuropathies (general features, genetic neuropathies, diabethic
neuropathy, diagnosis and avaluation of the peripheral nervous
system
Guillain Barre syndrome (poliradiculoneuritis)
Lumbar, sacrate and coccigeal plexus
Neuron
Motor neuron: functional
unit of the neuromuscular
system
Consist of
Lower motor neuron (anterior hornspinal cord; cranial nerve motor
nucleus-brain stem)
Axon of that neuron
Multiple muscle fibers it innervates
Neuron-to-muscle-fiber ratio:
•Muscles with highly refined
movements (extrinsic muscles of the
eye) (1:10)
•Coarse and stereotyped movements
(calf muscles) (1:1800)
Transmiterea informaţiei – depolarizare,
potenţial de acţiune
Canale de sodiu
Canal de potasiu
Canal de calciu
Synapse
Sinapsele pot fi localizate
oriunde – la nivelul dendritelor
(1), corpului celular (2),
axonului (3) sau terminatiilor
axonale (4)
Sinapsa
Normal peripheral nerve
Nerve fiber: principal
structural component of
peripheral nerve;
Composed of:
•Axon
•With its Schwann cells and myelin
sheath
A nerve consists of numerous
fibers that are grouped into fascicles
Myelinated and unmyelinated
nerve fibers are intermingled within the
fascicle
Three major connective tissue components of peripheral nerve
•Epineurium (encloses the entire nerve)
•Perineurium (encloses each fascicle)
•Endoneurium (surrounds individual nerve fibers)
macrofag
colagen
fibră
nemielinizată
fibră
mielinizată
elastină
limfocit
mastocit
fibroblast
capilar
neutrofil
substanţă
de bază
•Peripheral axons contain
organelles and cytoskeletal
structures (microfilaments,
neurofilaments etc)
•Protein synthesis does not
occur in the axon
•Axoplasmic flow
(anterograde) delivers
proteins and other
substances synthesized in
the perikaryon down the
axon
•Retrograde transport
system serves as a
feedback system for the cell
body.
Myelinated fiber in sural nerve (most commonly examined by biopsy)
2 to 16 µm in diameter
Smaller axons
•Average 4 µm
•Twice as numerous as the larger axons
Axons are myelinated in segments (internodes) separated by nodes of Ranvier
A single Schwann cell supplies the myelin sheath for each internode
Unmyelinated axons
Far more numerous than myelinated
axons
Range in size from 0.2 to 3 µm
Enveloped by Schwann cell cytoplasm
(5 to 20 axons in humans)
The Schwann cells
•Pale oval nuclei
•Elongated bipolar cell body
Myelin is composed of lipids and proteins
Pathology
General Reactions of the Motor Unit
Two main responses of peripheral nerve to injury:
•Diseases that affect primarily the Schwann cell - segmental
demyelination
•Involvement of the neuron and its axon leads to axonal degeneration
May be followed by axonal regeneration and
reinnervation of muscle
Two principal pathologic processes seen in skeletal
muscle
Denervation atrophy, which follows loss of axons
Myopathy primary abnormality of the muscle fiber itself
SEGMENTAL DEMYELINATION
Occurs
•Dysfunction of the Schwann cell (as in
Guillain-Barré Syndrome)
•Damage to the myelin sheath (e.g., in
hereditary motor and sensory neuropathy)
Random and multifocal
The denuded axon provides a stimulus for
remyelination
Newly myelinated internodes are shorter than
normal with thin myelin sheath
Onion bulbs:
Thinly myelinated axon surrounded by concentrically arranged Schwann cells
The result of demyelination and remyelination (chronic demyelinating neuropathies)
AXONAL DEGENERATION AND MUSCLE FIBER
ATROPHY
Axonal degeneration is the result of primary destruction of
the axon, with secondary disintegration of its myelin sheath.
May be
Focal (such as trauma or ischemia)
More generalized abnormality affecting
•The neuron cell body (neuronopathy) or
•Axon (axonopathy)
Wallerian degeneration
Much more prominent after focal injury
The distal part of the axon will initially degenerate
Sprouting axonal branches from the proximal part (axonal regeneration 1mm/day)
Reestablishing contact with the muscle fibers
With axonal degeneration there is denervation atrophy of the muscle fibers
within the affected motor unit
The atrophic fibers are smaller than normal and have a roughly triangular shape ("angulated").
Rounded zone of disorganized filaments in the center of the fiber (target fiber) –due to cytoskeletal reorganization
Reinnervation of atrophic muscle fiber:
From neighboring motor unit
Increased muscle fibers per motor unit
Peripheral nervous system
Disorders of the Peripheral
Nervous System
Polineuropathies
Diabetic neuropathy
Evaluation of peripheral neuropathies
Poliradiculoneuritis
Lumbar and sacrate plexus
Peripheral Neuropathy
 Any
disease of the peripheral nerves of
any cause
Polyneuropathy – distal symmetric distribution
 Mononeuropathy Multiplex – multifocal
random
 Mononeuropathy – single nerve involvement

Polyneuropathy
Pathologic involvement of peripheral
nerves usually due to acquired toxic and
metabolic states
 Manifestations:




Distribution – distal symmetrical (glovestocking distribution)
First symptoms tend to be sensory loss or
dysfunction (dysesthesias)
Signs and symptoms of lower motor neuron
disease (decreased DTRs, atrophy,
weakness)
Polyneuropathy
 Vary
in:
Rate of disease evolution
 Degree of severity
 Small fiber vs. large fiber involvement




Small fiber symptoms : pain and temperature
disturbances (numbness, painful paresthesias)
Large fiber symptoms and signs : weakness,
areflexia, sensory ataxia or loss of position and
vibration sense
Axonal vs. demyelinating
Common Causes of Polyneuropathy
 Diabetes
mellitus
 Uremia
 Vit.
B deficiency
 Critical illness
 Hypothyroidism
 Carcinomas
 HIV
Common Causes of polyneuropathy

Drugs

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Amiodarone
Antineoplastics
(cisplatin, vincristine)
Dapsone
Hydralazine
Isoniazid
Pyridoxine
Phenytoin
Metronidazole

Toxins



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
Arsenic
Diphtheria Toxin
Inorganic lead
Organophosphates
Thallium
Clinical picture



Motor
Sensory
Trophic
Pathogenical Classification of
polyneuropathy:



demielinating
axonal
mixt (diabetes, alcohol)
Classification of polyneuropathy:
Axonal

Acute – relatively uncommon

Massive intoxications – arsenic
Subacute – metabolic/toxic
 Chronic – 6 months- years


Hereditary neuropathies – slow course, absence of
positive symptoms, mainly motor, absence of
systemic disorder


Most are autosomal dominant but some are also autosomal
recessive
Metabolic/toxic
Classification of polyneuropathy :
Demyelinating
Acute – Guillain-Barre Syndrome (GBS)
 Subacute – all are acquired



Relapsing-remitting neuropathy (toxic)
Chronic –




Hereditary
Inflammatory -CIDP
Toxic
Metabolic
Polyneuropathies
 Genetic Neuropathies
 Most common is
–
autosomal dominant peroneal muscular
atrophy
Polyneuropathies
 Acquired
demyelinating
Acute : GBS – monophasic
 Chronic : CIDP – slowly progressive or
relapsing


May be treated with steroids, plasmapheresis and
immunosuppressants
Polyneuropathies

Diabetic Polyneuropathy


Due to long standing
hyperglycemia
May take almost any form
Polyneuropathies

Neuropathies of dysproteinemia




Multiple myeloma –especially of the osteosclerotic type
Benign monoclonal gammopathy
Infectious: Lyme disease, lepper
Neuropathies of HIV infection




Depends on the stage of the disease
GBS or CIDP- following seroconversion (asymptomatic)
Subacute to chronic mononeuritis multiplex (symptomatic)
Late symptomatic –distal symmetric sensory polyneuropathy or
asymmetric painful polyradiculopathy involving the cauda equina
caused by CMV
Polyneuropathies
 Autonomic
neuropathies

Usually part of the more generalized polyneuropathy

Symptoms usually negative (postural hypotension,
faintness, anhidrosis, hypothermia, bladder atony,
obstipation, sexual impotence, dry eyes and mouth)

Positive symptoms include paroxysmal tachycardia,
hypertension, diarrhea, hyperhidrosis
Polyneuropathies

Plexopathies

Causes:





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
Trauma
Cervical rib band
Malignant tumor infiltration
Radiation
Idiopathic
Upper brachial plexopathy: weakness,
atrophy and pain in the shoulder girdle and
arm
Lower brachial plexopathy: weakness,
atrophy and sensory loss or pain in the
distal arm and hand
Recovery
 The
PNS has an excellent ability to
regenerate
 2 months to years
 Depends on the nature of neuropathy
(axonal vs demyelinating)
 Depends on whether the cause of the
neuropathy has been eliminated
Treatment


Ethiological
Symptomatic




pain – carbamazepine, phenitoin, gabapentin,
pregabalin, triciclic antidepressants
Muscle cramps – baclofen (Lioresal),
benzodiazepines in small doses
Cauzalgia –alfa lipoic acid, eventually haloperidol,
levomepromazin
Nerve trophic substances (benfothiamine, alpha
lipoic acid, B vitamins)
Mononeuritis multiplex
 Simultaneous
or sequential involvement of
individual noncontiguous nerve trunks
 Multifocal and random
 1/3 demyelinating
 2/3 axonal
 Causes :
Vasculitis - 50% (PAN, SLE, RA, mixed CTD)
 Infectious –leprosy
 Granulomatous disease
 Idiopathic

Ereditary neuropathies
Hereditary neuropathies

HMSN I – Charcot Marie-Tooth



Most frequently encountered. AD
Demielinating type of Charcot-Marie Tooth disease
Peripheral nerve hipertrophy – “onion bulbs”





Starts between 5 and 20 years
Motor deficit is more important in lower limbs:
steppage; pes escavatum. Sensory deficits are
discrete. Autonomic damage (cold feet and legs,
livedo reticularis, other trophic changes, pupilary
abnormalities, heart rhytm abnormalities).
Essential tremor, OT reflexes are abolished,
enlargement of peripheral nerves
Associated with optic atrophy – HMSN type VI
Associated with retinitis pigmentosa – HMSN type
VII
HMSN I
Hereditary neuropathies

HMSN II –axonal type of CMT



AD
Debut 20-40 years old; no nerve hypertrophies.
HMSN III – Déjérine-Sottas





AD or AR
Hypo- de- and remielination; “onion bulb” aspect
Starts at 1-10 years
Developpment slowing; motor distal deficits and
atrophies; rapid sensory damage (parestesiae);
peripheral nerve enlargement; kyphoscoliosis,
nonreactive pupils and nistagmus, intelectual
impairment
Quickly evolving
Hereditary neuropathies

HMSN IV – Refsum disease




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Neuropatia ereditară sensibilă la
presiune (neuropatia tomaculară)

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AR; first symprtoms before 20 years;
Segmental demielination, “onion bulb”
aspect,
Retinită pigmentară, polineuropatie, ataxie
cerebeloasă, hipoacuzie, ihtioză, anosmie,
cardiomiopatie, tulburări ale scheletului
Dozarea acidului fitanic
AD; demielinizare segmentară; îngroşare
internodală în formă de cârnat
Decadele 2-3 de viaţă, paralizii recurente de
nervi periferici după compresiuni
Neuropatii ereditare senzitive şi
autonome

Afectarea preferenţială a fibrelor subţiri
Polineuropatia alcoolică



Degenerescenţă axonală (influenţa directă a alcoolului) cu
demielinizare secundară (malnutriţie)
Debut insidios (săptămâni/luni); ocazional acut – zile
Tulburări simpatico-motorii, senzaţie de arsură, durere la
compresiunea maselor musculare, crampe musculare, ataxia
mersului, mononeuropatii
Polineuropathies
Diabetic neuropathy
Evaluation of peripheral neuropathies
Poliradiculoneuritis
Lumbar and sacrate plexus
Diabetic Neuropathy



About 60-70% of people with diabetes
have mild to severe forms of nervous
system damage,
More than 60% of nontraumatic lowerlimb amputations in the United States
occur among people with diabetes.
Risk Factors


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
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Glucose control
Duration of diabetes
Damage to blood vessels
Mechanical injury to nerves
Autoimmune factors
Genetic susceptibility
Lifestyle factors – smoking, diet
Pathogenesis of Diabetic
Neuropathy

Metabolic factors


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High blood glucose
Advanced glycation end products
Sorbitol
Abnormal blood fat levels
Oxydative stress
Ischemia
Nerve fiber repair mechanisms
Both axonal and demielinative pathologic
processes
Classification of Diabetic
Neuropathy
 Somatic
neuropathy
 Symmetric
polyneuropathy
 Polyradiculopathy
 Mononeuropathy
 Autonomic
neuropathy
Symmetric Polyneuropathy



Most common form of
diabetic neuropathy
Affects distal lower
extremities and hands
(“stocking-glove” sensory
loss)
Symptoms/Signs




Pain
Paresthesia/dysesthesia
Loss of vibratory sensation
Amyotrophy
Polyradiculopathy

Lumbar polyradiculopathy
(diabetic amyotrophy)


Thoracic polyradiculopathy


Thigh pain followed by muscle
weakness and atrophy
Severe pain on one or both sides
of the abdomen, possibly in a
band-like pattern
Diabetic neuropathic cachexia


Polyradiculopathy + peripheral
neuropathy
Associated with weight loss and
depression
Mononeuropathy

Peripheral mononeuropathy




Single nerve damage due to compression
or ischemia
Monophasic evolution
Occurs in wrist (carpal tunnel syndrome),
elbow, or foot (unilateral foot drop)
Mononevritis multiplex – random
involvement of several unrelated
nerves
Mononeuropathy

Cranial mononeuropathy


Most frequently oculomotory
nerves ( III, VI şi IV), facial
nerve, optic nerve (optic
anterior ischemic neuropathy)
Diabetic oftalmoplegia


Rare
Rapid evolution (1-2 days),
with painful ophtalmoplegia
Autonomic neuropathy

Affects the autonomic nerves controlling
internal organs





Peripheral
Genitourinary
Gastrointestinal
Cardiovascular
Is classified as clinical or subclinical based
on the presence or absence of symptoms
Autonomic neuropathy

Cardiovasculary



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
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Tachicardia, diminished
tolerance for effort
Cardiac denervarvation
Ortostatic hypotension
Gastrointestinal

Esophageal dysfunction
Gastroparesis diabetica
Diarhea
Constipation
Incontinence
Urogenital


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Erectile dysfunction
Retrograd ejaculation
Cistopathy
Neurological bladder
Neurovasculary

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Metabolic and hypotalamic

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Intolerance to heat
Gustative sudation
Dry skin
Unnoticed hypoglicemia
Lack of response to
hypoglicemia
Autonomic dysfunction in
connection to hypoglicemia
Pupilary

Argyll-Robertson sign
Treatment


Strict glycemic control
Intervention on pathogenic pathways:





Aldoz-reductase inhibitors –block the calea polyol pathway
Alpha lipoic acid (600-800 mg/zi)
Gamma linolenic acid
NGF (possibly)
Preventing/improvement of symptoms: analgetics,
antidepressants



Tryciclic antidepressants,
Gabapentin
Pregabalin
Complications of Polyneuropathy


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
Ulcers
Charcot arthropathy
Dislocation and stress fractures
Amputation - Risk factors include:



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
Peripheral neuropathy with loss of protective
sensation
Altered biomechanics (with neuropathy)
Evidence of increased pressure (callus)
Peripheral vascular disease
History of ulcers or amputation
Severe nail pathology
Diabetic foot



Joint and tegumentary lesions in patients with
neuropathy and/or peripheral vascular disease
40-60% of non traumatic amputations
30-50% of amputees will repeat the procedure for the
opposite limb during the next 1-3 years.
Motor
neuropathy
Sensory
neuropathy
Autonomic
neuropathy
- shape changess of foot
- overcharging of pressure points
- repeated microtrauma
- lack of pain
-Not using the defense
mechanisms
- altered skin reaction
mechanisms
-Altered skin mycrocirculation
Ulcerations
Polineuropathies
Diabetic neuropathy
Evaluation of peripheral neuropathies
Poliradiculoneuritis
Lumbar and sacrate plexus
Diagnostic Tests


Clinical examination
Nerve conduction studies
Evaluation



Calibrated tuning fork
Semmes–Weinstein Monofilaments
Quantitative sensory testing (electrical,
thermal, vibratory, sensory treshold)
Electrodiagnostics


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Objective proof of lesions
Quantitative evaluation
Spreading and type of nerve damage
Electrodiagnosis : EMG-NSS

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Neurophysiologic study
Neuropathy vs. myopathy
Localization of lesion in the AHC, root, plexus, or distal
nerve trunk, NMJ, muscle
Generalized polyneuropathy or multifocal neuropathy
Upper vs. lower motor neuron disease
Axonal vs. demyelinating neuropathy
Activity (acute, chronic, regenerating)
If in the peripheral nerve trunk, the site of the lesion
Electromyogram – Nerve Stimulation
Studies (nerve conduction velocity)
Nerve Biopsy
Done in the sural nerve
 Indicated for : asymmetric and
multifocal neuropathic
disorders
 In diseases characterized by
nerve enlargements
 In establishing the diagnosis in
some genetically determined
disorders

Other tests


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Genetical
Autonomic tests (heart rate variability)
CSF
Polineuropathies
Diabetic neuropathy
Evaluation of peripheral neuropathies
Poliradiculoneuritis
Lumbar and sacrate plexus
Guillain Barre syndrome
Guilllain Barre Syndrome (GBS)
GBS is defined as
“a syndrome of acute weakness of the limbs and reduced or
absent reflexes, with or without sensory loss attributable to a
disorder of the peripheral nerves not due to systemic
disease” (Hughes. 1990).
GBS is a clinical diagnosis though there are frequently
abnormal laboratory features including an elevated CSF
protein and evidence of peripheral nerve demyelination
(Hughes. 1994; Hartung et al. 1998).
Guillain-Barre Syndrome


An acquired disease of the peripheral
nervous system
Clinical:




Major features: weakness and areflexia
The most common cause of acute flaccid
paralysis in all ages.
No specific test to confirm the diagnosis
A syndrome rather than a disease
The typical illness evolves over weeks
usually following an infectious disease:


1. Paresthesiaes
usually hearld the
disease
2. Fairly symmetric
weakness in the legs,
later the arms and,
often, respiratory and
facial muscles

3. Diminution and
loss of the DTRs

4. Albuminocytologic
dissociation

5. Recovery over
weeks to months
Jean-Baptiste Octave Landry
Georges Guillain
Guillain, Barre & Strohl 1916
Revue Neurologique
Two soldiers in Amiens developing
paralysis and loss of DTRs.
A new diagnostic feature:
albuminocytologic dissociation in
the CSF
No mention of Landry
Guillain-barre Syndrome
Clinical features


Progressive weakness and diminished
deep tendon reflexes in a symmetric
distribution.
Ascending progression – most common


5 – 10% upper >> lower
5-10% proximal >> distal
Guillain-barre Syndrome
Clinical features




Sensory disturbances: pain or paresthesias
Cranial nerves
Autonomic disturbances – infrequent but life
threatening.
15-20% progress to respiratory failure.
Clinical features

Stages:



Progression phase- days to weeks, max. 6
weeks. Period of major complications
Plateau phase - days to weeks
Recovery – weeks to months
Laboratory findings:

CSF


normal cell count – up to 10 lymphocytes
elevated protein – 80-200 mg/dl , after 1 week
Laboratory findings

Electrophysiological tests:



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80% abnormal studies
Multiple nerves must be studied
Evidence of multifocal demyelination in motor and
sensory nerves.
prolonged distal latency
Reduction of the F WAVE response and H-REFLEX.
H REFLEX – single most sensitive test for early
GBS, absent in 97% of pts in the first week
(Gordon at al. neurol 2001)
Pathophysiology


Immune mediated disease
Possible mechanism: autoAB bind to
glycoproteins on peripheral myelin ,
causing a cascade of events which
eventually destroy the myelin.
Pathology
Depend upon the form of GBS.
AIDP and MILLER-FISHER:
 Inflammation and demyelination
 More severe inflammation at the junction of dorsal and ventral
roots at the site of the dural attachment.
 Secondary axonal degeneration
Motor and motor-sensory variants:
 Axonal degeneration without an inflammatory response
 The immune process is directed at the nodes of Ranvier
 No demyelination
Pathophysiology

50 – 70% have an antecedent illness
within the previous 4 weeks.
URTI, gastroenteritis
 C. Jejuni – more severe symptoms
 CMV, EBV
Immunizations:
 “swine flu” vaccine (1976)
 Rabies vaccine

Infectious
Systemic


Viral: Influenza, Coxsackie,
EBV, Herpes, HIV, Hepatitis,
CMV, WNV

Bacterial: Campylobacter
jejuni, Mycoplasma, E. coli

Parasitic: Malaria,
Toxoplasmosis




Hodgkins
Hyperthyroidism
Sarcoidosis
Collagen Vascular d.
Renal d.
Other events:





Surgery
Immunization
Pregnancy
Envenomization
Bone marrow transplantation
Therapy


Supportive
Monitoring: BP, HR, RR, TEMP.



Frequent physical examinations to establish a
trend.
Serial lung function testing
If dysphagia or shoulder weakness:
respiratory assistance may be necessary.
Therapy

Indications for transfer to ICU:





Respiratory failure
Autonomic dysfunction
Bulbar dysfunction
Bilateral facial weakness
aspiration
Therapy

Corticosteroids:


First immunotherapy for GBS
“Corticosteroid medications do not seem to
help improve symptoms or lessen nerve
damage from Guillain-Barre syndrome” - The
Cochrane Database of Systematic Reviews 2000 (6
RCT’s, 195 pts treated with steroids vs 187 pts with
supportive care)

No indication as monotherapy, evidence of
benefit if added to IVIG.
Therapy

Plasma exchange






reduce length of stay in the ICU and in hospital
Reduce need for and period of ventilation
Reduce length to unaided walking and neurological
sequele.
4 double-volume exchanges on alternate days over 1
week.
exchange with albumin 5%
more beneficial when started within seven days of the
disease onset.
Therapy

IVIG




Probably same effects as plasma exchange
or even superior
More available, less side effects
2 g/ Kg over 2-4 days
Caution: early transient relapse after IVIG
administration
Prognosis



3% mortality
Recovery- 1-6 months
80% have complete recovery in 12 months
Polineuropathies
Diabetic neuropathy
Evaluation of peripheral neuropathies
Poliradiculoneuritis
Lumbar, sacrate and coccigeal plexus
Distribution of roots
from the Lumbar and
Sacral Plexuses






Hip Flexion
 L 1, 2, 3
Knee Extension
 L 2, 3, 4
Foot Dorsiflexion
 L 4,5
Foot Plantar Flexion
 S1, 2
Knee Flexion
 L5, S1, S2
Hip Extension
 L5, S1, S2
Dermatomes of the Leg
Clinical Principles

Detecting subtle
weakness

Quadriceps/Gluteus
maximus
Stand on tip toes



Get up from squat


Reflexes
Gastrocnemius/Soleus
Stand on heels

Tibialis Anterior

Knee Jerk - evaluates
 Quadriceps muscle
 Femoral Nerve
 Primarily L4 nerve root
(also L2, L3)
Ankle Jerk - evaluates
 Gastrocnemius muscle
 Tibial Nerve
 Primarily the S1 nerve
root (also S2)
Lumbar Plexus



Formed by the anterior
rami of L1-L4.
Supplies the anterolateral
abdominal wall, external
genitals, and part of the
lower limbs.
Femoral nerves,
obturator nerves.
Copyright 2009, John Wiley & Sons,
Inc.
Sacral Plexus




Formed by the anterior
rami of L4-L5 and S1-S4.
Supplies the buttocks,
perineum, and lower
limbs.
Gives rise to the largest
nerve in the body- the
sciatic nerve.
Lies in pelvic cavity,
anterior to sacrum and
piriformis

Branches




Superior gluteal
Pudendal
Posterior femoral
cutaneous
Sciatic
Hip (coxal) joint / GLUTEAL MUSCLE
GROUP FUNCTIONS
Gluteus maximus
Powerful hip extensor
Functions:
•Climbing
•Walking uphill
•Regaining upright posture from
squatting
•NOT in normal walking
Coccygeal Plexus


Formed by the
anterior rami of S4-S5
and the coccygeal
nerves.
Supplies a small area
of skin in the
coccygeal region.
Copyright 2009, John Wiley & Sons,
Inc.
Obturator nerve

Enters thigh through
obturator foramen;

Supplies medial group of
muscles of thigh, obturator
externus, and skin of
medial side of thigh