DISEASES OF THE PNS

Rosales, MD

I. Peripheral Nervous System

II. Peripheral Neuropathy
III. Pathologic Reactions
IV. Guillain Barre Syndrome
V. Myasthenia Gravis
VI. Myopathy
VII. Diseases of the Cranial Nerves

PERIPHERAL NERVOUS SYSTEM

Composition
– structures outside of the pial membrane of the spinal cord and
brainstem

Symptoms SYMPTOMS OF PERIPHERAL NEUROPATHY

– pure motor
o neuromuscular junction
MOTOR
o muscle
– mixture of motor / sensory / autonomic
o Cranial nerve Positive (Added) Negative
o Spinal nerve root – Muscle cramps – Weakness of distal toe and
o Spinal nerve – Fasciculation ankle extensors
o Plexus – Myokymia – Atrophy
o Peripheral nerve – Tremor – Gait disturbance

Predominantly Motor Symptoms

PERIPHERAL NEUROPATHY
– Damage to the nerves of the PNS, which maybe inherent to the
nerves or from involvement in a systemic illness.
1. AIDP / CIDP
2. Hereditary Sensory Motor neuropathy
3. Toxic neuropathy (lead, organophosphate)
4. Neuropathy due to systemic condition (porphyria,
osteosclerotic myeloma, hypoglycemia)

SENSORY

Disordered Function (Positive) Loss of Function (Negative)

– Paresthesia – Large fiber decreased:
– Hyperalgesia vibration, proprioception,
– Allodynia reflexes
– (+) Romberg’s
– Small fibers: numbness (pain
and temperature)

Predominantly Sensory Symptoms

1. Diabetes
2. AIDS (ganglionopathy)
3. Vitamin B12 deficiency
4. Toxicity with cisplatin, thalidomide (ganglionopathy)
5. Pyridoxine toxicity (ganglionopathy)
6. Paraneoplastic (ganglionopathy)

Patterns of Sensory Loss

1. Polyneuropathy
a. symmetrical, distal
b. legs > arms
c. may involve face

2. Severe Axonal Neuropathy

a. Escutcheon pattern of sensory loss over abdomen
and thorax

3. Sensory Ganglionopathy
a. sensory loss of trunk, scalp, face due to simultaneous
damage of proximal and distal part of sensory nerve

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 – distally predominant
AUTONOMIC DYSFUNCTION – usually symmetrical
– stocking – glove sensory loss
1. Orthostatic lightheadedness – distal muscle wasting and weakness
2. Fainting spells
3. Sweating (reduced or excessive) DIABETIC NEUROPATHY
4. Heat intolerance – large fiber
5. Bladder, bowel and sexual dysfunction o proprioception, vibration, light touch
6. Anorexia, early satiety, vomiting – small fiber
o impaired pain / temperature
Predominantly Autonomic – autonomic
– Acute o cardiovascular and GI
o GBS – commonly presents with slow onset numbness and tingling
o Porphyria then pain in distal extremities; feet before hands
o Vincristine, Rodenticide – early absence of DTRs; distal weakness later
o Acute Pandysautonomic neuropathy – cranial nerve deficits: EOM with pupillary sparing
(idiopathic, paraneoplastic) – focal entrapments or ischemic neuropathies
– Chronic – Amyotrophy
o DM o asymmetrical proximal leg weakness and pain
o Amyloid
o HIV
o Paraneoplastic PATHOLOGIC REACTIONS
o HS and Autonomic neuropathy

PERIPHERAL NERVE
PERIPHERAL NEUROPATHY: BY COURSE

ACUTE SUBACUTE CHRONIC RELAPSING /

(days to 4 wks) (4-8 weeks) (>8 weeks) REMITTING
GBS Toxins / Meds HSMN GBS
Porphyria Nutrient Inherited CIDP
Deficiency Sensory
neuropathy
Critical Illness Metabolic CIDP HIV / AIDS
Thallium Paraneoplastic, Toxin /
CIDP Porphyria

CLINICAL PATTERN

ANATOMIC CLASSIFICATION
1. Mononeuropathy
2. Plexopathy (brachial, lumbar, sacral)
3. Radiculopathy (cervical, thoracic, lumbosacral)
4. Multiple neuropathy (Mononeuropathy Multiplex)
5. Polyneuropathy
6. Polyradiculoneuropathy PATHOLOGY
– Myelin sheath
MONONEUROPATHY o most vulnerable to injury
– focal involvement of a single nerve – Wallerian Degeneration
o due to local process: o dying forward (nerve degenerates from point of
 Direct trauma axonal damage outward)
 Compression or entrapment – Axonal Degeneration
 Vascular lesions o dying backward (from distal to proximal)
 Neoplastic compression or infiltration o most common reaction of PN
o seen in metabolic & toxin exposure
MONONEUROPATHY MULTIPLEX – Axonal Reaction
– simultaneous / sequential damage to multiple noncontiguous o nerve body destruction in response to axonal injury
nerves
o due to: DEMYELINATING NEUROPATHY
 Ischemia caused by vasculitis – seen in immune-mediated disorders
 Microangiopathy (DM) – faster recovery than axonal disorder
– mild sensory loss with prominent muscle weakness which can
POLYNEUROPATHY start proximally
– evolution is centripetal: spread up legs; early symptoms are – absent reflexes, slowed conduction, elevated CSF protein
usually sensory – neuropathic tremors / palpably enlarge nerves
– usually depressed ankle jerk
– poor: walking on heels

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CLUES FROM GS AND VS Nerve Biopsy
– Pulse & BP – in vasculitis, amyloid neuropathy, leprosy, CIDP, inherited
o Resting tachycardia disorders of myelin and rare axonopathies
o HR unresponsive to exercise – the SURAL NERVE is selected most commonly
o Orthostatic hypotension without tachycardia – the Superficial Peroneal nerve
o Hypertension – CKD o alternative;
– RR o advantage of allowing simultaneous biopsy of the
o GBS peroneus brevis muscle through the same incision
– Anemia – this combined nerve and muscle biopsy procedure increases
o Vitamin B12 deficiency the yield of identifying suspected vasculitis
o CKD
– Goiter
o Hypothyroidism
– Skin and skeletal changes
o DM
o Leprosy
o Amyloid
o Connective tissue
o Toxin

DIAGNOSIS

History & PE
– 7 Questions
o Systems (fibers) involved?
o Distribution?
o Nature of sensory / motor / autonomic involvement?
o Evidence of UMN involvement?
o Temporal involvement?
o Evidence of hereditary neuropathy?
o Associated medical conditions?
GUILLAIN BARRE SYNDROME
– Autonomic studies include determination of
o Heart rate variation with respiration – worldwide; no sex nor age predilection
o Heart rate response and blood pressure to – 1.7 to 4 cases / 100,000/year
standing/tilting – MALES> FEMALES
o Blood pressure response to sustained hand grip – ADULTS> CHILDREN
o Measure of sympathetic skin response – 2/3 of patients have infection 3 weeks prior to symptoms (GI or
respiratory); vaccination
– Campylobacter jejuni
o most common isolate
– May be due to CMV, EBV, M. pneumoniae, H. influenza
– Antecedent symptoms :
o 52% fever
o 48% cough
o 39% sore throat
o 30% nasal discharge
o 27% diarrhea

C. jejuni isolates from patients express lipo-oligosaccharides (LOS) that

mimic the carbohydrates of gangliosides (ganglioside- like LOS) → cross
reaction → local complement activation at the damaged nerve → clinical
symptoms

Anti GBq ab as Complement

GM1 on
part of mediated injury at
nerve, nodes
molecular Paranodal axon-glial
of ranvier
mimicry junction

Disrupts the
Conduction
flaccid paralysis cluster of sodium
block channels

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 Features that should raise about the diagnosis*:
– severe pulmonary dysfunction with limited limb weakness at
onset
– severe sensory signs with limited weakness at onset
– bladder or bowel dysfunction at onset
– fever at onset
– sharp sensory level
– slow progression with limited weakness without respiratory
involvement (consider subacute inflammatory demyelinating
polyneuropathy or CIDP)
– marked persistent asymmetry of weakness
– persistent bladder or bowel dysfunction
– increased number of mononuclear cells in CSF (>50x106/L)
– polymorphonuclear cells in CSF
CLINICAL MANIFESTATIONS – *adapted from Asbury and Cornblath
– areflexic motor paralysis with or without sensory disturbance
VENTILATOR ASSISTANCE
– ascending paralysis proceeding from hours to days
– legs > arms – among severely affected patients (who’s unable to walk), about
– facial diplegia – in 50% 25% need artificial ventilation.
– pain in the shoulder / back / neck / leg – Indications for intubation:
– difficulty swallowing – VC of 15ml/kg
– proprioceptive sense affected – significant hypercarbia, hypoxia
– plateau (within 4 weeks of onset) – Death is not due to ventilatory insufficiency but due to
intercurrent infection, MI or pulmonary embolism
CLINICAL FEATURES – serious infections occur in 60% of those on the ventilator for >
3weeks
– Cardiovascular autonomic instability
o Unstable blood pressure
o Postural hypotension
Relation between infections, antiganglioside antibodies,
o Cardiac dysrhythmias
And clinical course of GBS
– Dysautonomia
– Respiratory depression

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GBS VARIANTS MYASTHENIA GRAVIS

ANATOMY

Neuromuscular Junction (NMJ)

– Components
o Presynaptic membrane
o Postsynaptic membrane
o Synaptic cleft
– Presynaptic membrane contains vesicles with Acetylcholine
(Ach) which are released into synaptic cleft in a calcium
dependent manner
– Ach attaches to Ach receptors (AchR) on postsynaptic
membrane
Other axonal
AIDP AMAN
forms

Schwann cell Preterminal Axonal

membrane motor endings membrane

Demyelination,
Degeneration of Axonal
Conduction block,
motor endings degeneration
See axonal degen

Rapid Slow
Remyelination
Regeneration regeneration

Rapid recovery Rapid recovery Slow recovery

RECURRENT GBS
– 2 or more episodes of GBS (NINCDS criteria) with a minimum
time between episodes of 2 months (full recovery in between)
or 4 months (only partial recovery)
– the clinical symptoms remain similar, but severity of the
symptoms and the nature of the preceding infections vary.
– patients are younger (<30 yrs.) and more often had MFS
– genetic or immunological host factors may play an important
role, since these patients can develop similar symptoms after
different preceding infections

IMMUNOTHERAPY
– IVIG or plasmapheresis can be initiated as they are equally
effective
– combining these therapies has no additional benefit
– meta-analysis of RCTs indicates that:
o PE reduces need for mechanical ventilation from
27% to 14%
o Increases likelihood of full recovery at 1 yr. from 55% CLINICAL PRESENTATION
to 68%
– best documented of effect of these agents is to shorten time to Ocular muscle weakness
recovery – Asymmetric
– no effect on mortality o Usually affects more than one extraocular muscle
and is not limited to muscles innervated by one
STEROIDS cranial nerve
o Weakness of lateral and medial recti may produce a
– Explanation for this ineffectiveness is unclear:
o steroids may have minimal effect n the toxicity of pseudointernuclear ophthalmoplegia
 limited adduction of one eye with
anti-ganglioside antibodies and subsequent
complement activation nystagmus of the abducting eye on
o may adversely affect macrophages that clear myelin attempted lateral gaze
debris thus hampering remyelination – Ptosis cause by eyelid weakness
– Diplopia is common

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Bulbar muscle weakness
– Palatal muscles
o “nasal voice”, nasal regurgitation
o Chewing may become difficult
o Severe jaw weakness may cause jaw to hang open
o Swallowing may be difficult and aspiration may occur
with fluids – coughing and choking while drinking
– Neck muscles
o Neck flexors affected more than extensors

Respiratory muscle weakness

– Weakness of the intercostal muscles and the diaphragm may
result in CO2 retention due to hypoventilation
o May cause neuromuscular emergency
– Weakness of pharyngeal muscles may collapse the upper
airway
o Monitor negative inspiratory force, vital capacity and
tidal volume
o Do not rely on pulse oximetry
 Arterial blood oxygenation may be normal
while CO2 is retained

Limb muscle weakness

– Upper limbs more common than lower limbs

Upper Extremities Lower Extremities

Deltoids Hip flexors (most common)
Wrist extensors Quadriceps
Finger extensors Hamstrings
Triceps > Biceps Foot dorsiflexors
Plantarflexors

PROGRESSION OF DISEASE
– Mild to more severe over weeks to months
– Usually spreads from ocular → facial → bulbar → truncal →
limb muscles
– The disease remains ocular in 16% of patients
– Death rate reduced from 30% to <5% with pharmacotherapy
and surgery

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MODIFIED OSSERMAN’s CLASSIFICATION – Pyridostigmine is the most widely used
– Class 1 – onset: 15 – 30 mins and lasts for 3 – 4 hrs.
o Patients with ocular involvement alone – dose: 30 – 60 mg, 3-4x daily
– Class 2 – frequency of the dose should e tailored to the patient’s
o Mild weakness, not incapacitating without individual requirements throughout the day
oropharyngeal or respiratory muscle involvement
– Class 3 IMMUNOSUPPRESSION
o Moderate weakness, not incapacitating including – is required in nearly all patients with:
oropharyngeal and respiratory muscle weakness o Late onset MG
– Class 4 o Thymoma MG
o Incapacitating weakness of any muscle system incl. o MuSK MG
oropharyngeal& respiratory muscle weakness – suppress autoantibody production & its detrimental effects at
– Class 5 NMJ
o Life-threatening respiratory insufficiency requiring
ventilatory assistance GLUCOCORTICOIDS
– first & most commonly used immunosuppressant
– used when symptoms of MG are not adequately controlled by
MYASTHENIC CRISIS cholinesterase inhibitors alone
– exacerbation of weakness – endanger life – MOA: inhibits MHC expression and IL-1 production → ↓ IL-2
– respiratory failure and IFN γ production
o diaphragmatic and intercostal muscle weakness
– cause intercurrent infection Prednisone
– cholinergic crisis – most commonly used
o excessive anticholinesterase medication – decreases the severity of Mg exacerbations
– transient worsening might occur initially
– clinical improvement 2-4 weeks
TREATMENT – marked improvement in 40%
– remissions are noted in 30%
There are four basic therapies:
– Symptomatic treatment
THYMECTOMY
o acetylcholinesterase inhibitors
– Rapid short term – carried out in all patients with generalized MG aged between
o plasmapheresis and intravenous IG puberty and 55 years
– Chronic long term – Thymoma
o immunomodulating treatment: o surgical removal is a must; possibility of local tumor
 glucocorticoids spread
 immunosuppressive drugs – up to 85% of patinets experience improvement after
– Surgical treatment – of these, ~35% achieve drug-free remissions

PLASMAPHERESIS
– removes AchR Ab from the circulation DIAGNOSIS
– rapidly improves strength

Used for:
– short term intervention
– sudden worsening of myasthenic symptoms
– chronic intermittent treatment for refractory cases
– typically, one exchange is done every other day for a total of 4
– 6 times
– improvement is noted in a couple of days, but it does not last
for more than 2 months
– complications
o hypocalcemia,
o hypomagnesemia,
o hypothermia,
o hypotension
o transfusion reactions

INTRAVENOUS IMMUNOGLOBULIN THERAPY

– rapid improvement
– severe myasthenic weakness
– dose is 2g/kg over 5 days (400mg/kg/day)
– improvement occurs in ~70% of patients
– adverse reactions include headache, fluid overload, and rarely
aseptic meningitis or renal failure

ANTICHOLINESTERASE MEDICATIONS

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 MYOPATHY

Diseases of the Muscle

– Myopathy vs. Dystrophy
– Hypothyroidism
o weakness, cramps, pain and stiffness,
o muscle hyperthrophy,
o slow contraction and relaxation (25%);
o CK elevated
– Hyperthyroidism
o proximal weakness with atrophy may affect the
bulbar muscles
o Ck levels normal
– Hyperparathyroidism
o proximal muscle weakness,
o brisk reflexes,
o CK normal or slightly elevated
– Hypoparathyroidism
o symptoms due to tetany,
o hyporeflexia,
o CK levels elevated

Adrenal disorders
– Glucocorticoid excess causes myopathy associated with muscle
wasting
– Hyperaldosteronism (Conn’s) – potassium depletion

PROGNOSIS
– Untreated MG carries a mortality rate of 25-31%
– Treated MG has 4% mortality rate
– 40% have ONLY ocular symptoms
o Only 16% of those with ocular symptoms at onset
remain exclusively ocular at the end of 2 years

COMPLICATIONS
– Respiratory failure
– Dysphagia
– Complications secondary to drug treatment
o Long term steroid use
 Osteoporosis,
 cataracts,
 hyperglycemia,
 HTN
 Gastritis,
 peptic ulcer disease
 Pneumocystis carinii

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 DISEASES OF THE CRANIAL NERVES

TRIGEMINAL NEURALGIA

– UNILATERAL, PAROXYSMAL
– Second and 3rd division of CN 5
– Presence of an initiating or trigger point
– No sensory or motor dysfunction
– Usually idiopathic
– Disorder of middle age and later life
o Compression by superior cerebellar artery
o Age related brain sagging
CHRONIC THERAPY o Increased vascular thickness and tortuosity

Carbonic Anhydrase inhibitors

– Diamox (acetazolamide)
– Daranide (dichlorphenamide)
– Glauctabs (methazolamide)

Potassium-sparing diuretics
– Inspra (eplerenone)
– Aldactone (spironolactone)
– Dyrenium (triamterene)
o CAREFUL: NOT DYAZIDE, which has potassium-
wasting hydrochlorthiazide
– Midamor (amiloride)

Experimental
– 3,4 – Diaminopyridine BELL’S PALSY
– Pinacidil
– abrupt onset maximal weakness in 48
hours
– preceded by pain behind the ear
– hyperacusis, loss of taste sensation
– reactivation of HSV Type 1 and HZV
– treatment PREDNISONE 60-80 mg during
the first 5 days and tapered in the next 5
days

*********END OF LECTURE*********

Reference: PPT

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