Theme week 1 and 2 – Neurology and Neurosurgery
Polyneuropathy
Polyneuropaty is a condition of the peripheral nerves characterized by the fact that it is symmetrical,
more distal than proximal, often more sensory than motor and often the legs are more affected than
the arms. Symptoms are numbness, paresthesia often accompanied by pain and weakness.
Epi
The overall prevalence of polyneuropathy in the general population seems around 1 % and rises to
up to 7 % in the elderly. It seems more common in Western countries and females are more often
affected.
Pathophysiology
The peripheral nervous system is comprised of structures that lie outside the membranes of the
brain stem and spinal cord. Each axon in the peripheral nervous ssystem is an elongation of a nerve
cell that lies either in the CNS (anterior horn) or in a ganglion (dorsal root ganglion, sensory). Axons,
as you might remember are insulated by myelin made by the Schwann cell membrane with nodes of
Ranvier. The dorsal roots carry sensory information about: pain and temperature, simple touch,
discriminatory sensation (proprioception, vibration). The anterior horns have alpha motor neurons
(muscle) and gamma motor neurons (intrafusal muscle fibers of the spindles). Peripheral nerves are
composed of many axons bound together by connective tissue. We have type A fibers which are
myelinated and fast for motor and sensory (proprioception), then B thinly myelinated for ex. Pain
and temperature and ANS which are a bit slower and the smallest are C which are unmyelinated,
sensory for pain and temperature and slow.
Damage can occur to the axon, myelin sheath, cell body, supportive connective tissue, nutrient blood
supply to nerves. We see three types of pathologic processes:
- Wallerian degeneration: distal to injury the axon disintegrates, however we can get
regeneration since the base membrane of the Schwann cell surives and is a skeleton for axon
re-growth.
- Segmental demyelination: scattered distruction of the myelin sheath without axonal damage,
recovery will be good.
- Distal axon degeneration damage to the cell body or the action will lead to cell death and
loss of myelin. Re-innervation can only occur from surrounding nerves.
We can classify the polyneuropathies by etiology:
- Acute <4 weeks
o Inflammatory → demyelinative with lymphocytic infiltration → motor/ANS
o Diphteria → demyelinative, no infiltration. → cranial nerves, mixed
o Porphyria → axonal → motor, ANS
- Subacute (or chronic)
o Infections (HIV and leprosy) → inflammatory
o Vasculitis (PAN, Wegeners, Churg-strauss,non-systemic vasculitis) → Wallerian
degeneration
, o Metabolic/endocrine (diabetes, uremia, hypothyroidism, acromegaly) → axonal
degeneration → distal, sensorimotor, symmetrical
o Nutritional deficiencies (vitamin B1, alcohol, B12) → axonal degeneration with
segmental demyelination → sensory, weakness
o Malignancy (paraneoplastic, infiltration)→ axonal (can be with antibodies)
o Paraprotein associated gammopathy (IgG, IgA) → axonal with segmental
demyelination → sensorimotor
o Chronic inflammatory demyelinating polyneuropathy
o Amyloid deposition
o Inherited (charcot-Marie-Tooth disease, Refsum’s disease)
o Medication: antibiotics, oncology drugs, HIV, amiodarone, gold, phenytoin
o Toxins: solvents and heavy metals
Finally there is chronic idiopathic axonal neuropathy, this is about 20% of the patients where no
cause is identified. Symptoms progress slowly but patients do not develop significant disability.
It is important to distinguish axonal and demyelinating polyneuropathy since many causes of
demyelinating polyneuropathy are treatable.
Risk
Risk factors differ across countries. In developing countries there are communicable diseases
(leprosy) and in Western countries risk factors which are often the cause of polyneuropathy are
diabetes, alcohol overconsumption, cytostatic drugs and CVD. 20% of polyneuropathies remains
idiopathic. Prevalence has been increasing over the years.
Clinical presentation
Polyneuropathy usually develops over several months. It can also develop quicker as seen in for
example vasculitis or Guillain-Barré.
Negative phenomena: loss of sensation. Disease of the large myelinated fibres will give loss of touch
and joing position perception ‘cotton wool feeling’ of hands and feet as well as unsteady gait.
Disease of the small unmyelinated fibres will give loss of pain and temperature appreciation (ex.
Charcot joint =painless traumatic deformity).
Positive phenomena:. Disease of the large myelinated fibres produces paresthesia, which is a ‘pins
and needles’ sensation and disesae of the small unmyelinated fibres produces painful positive
phenomena: hyperalgesia (increased sensitivity to pain stimulus), hyperaesthesia (increased
sensitivity to any stimulus), hyperpathia (increased sensitivity to repetitive simulation), allodynia
(pain provoked by non painful stimulus).
Motor: weakness, usually more in the extensor muscles. Twitching of muscles (fasciculation) may be
felt and cramps. Absence of reflexes.
Autonomic: cold blue extremities, cutaneous hair loss, occasionally brittle finger or toe nails, poor
wound healing, dry skin, orthostatic hypotension, cardiac arrhythmia, impaired intestinal function,
impotence.
,Diabetic neuropathy
Diabetes (type 1 and 2) is the most common cause of neuropathy in the Western world. Over time
50% of people with diabetes will develop symptoms of polyneuropathy, mainly sensory, which might
be accompanied by pain and paresthesia. A proportion of patients develops autonomic neuropathy
which manifests as: orthostatic hypotension, tachycardia, hypotonic bladder, imporence, diarrhea
and poorly reactive pupils. Diabetes can also cause multiple mononeuropathies which can affect the
femoral nerve and oculomotor nerve in particular. Probably the casue is both vascular and metabolic
and therefore medication and monitoring of diabetes patients is key. Important complication:
neuropathic diabetic foot: impaired sensation, impaired ANS function with hot, very well perfused
skin of the feet and reduced sweating. This can result in changes in shape of the foot → abnormal
pressure load → ulcers noticed late due to the fact that the patient does not feel pain.
The pathogeneis of diabetic neuropathy is multifactorial.
First there are several metabolic factors. Due to high glucose in blood and tissues we see that AGE’s
(advanced glycation end products) are formed which are glycated proteins, they can cross-link and
cause microvascular complications. Glucose inside the cell is metabolized in part to sorbitol by aldose
reductase. Sorbitol can accumulate in the cell and deplete NADPH, increase osmolality which
interferes with cell metabolism and predisposes to oxidative stress. Furthermore, excess glucose
shunts glycolytic intermediates into the hexosamine pathway which produces urine diphosphate N
acetyl glucosamine. This molecule modifies TF’s essential for normal cell function, which is thus
disrupted. Protein kinase C is also activated due to the fact that glucose is converted to
diacylglycerol. PKC produces vasoconstriction and nerve hypoxia. High glucose activates the poly
(ADP-ribose) polymerase PARP enzyme in the cell nucleus which starts a process resulting in free
radical formation. Then finally we see that via multiple pathways hyperglycemia results in oxidative
stres and accumulation of ROS which leads to peripheral nerve damage.
Secondly there is nerve ischemia which is thought to be related to more focal neural loss, however
we also see thickened endoneurial blood vessel walls and occlusions at autopsy.
Thirdly peripheral nerve repair is impaired in diabetes. Maybe due to disease-induced loss of
neurotrophic peptides that normally mediate nerve repair like NGF, BDNF, neurotrophin 3, IGF,
VEGF. Insulin itself is also a neurotrophic factor.
Treatment consists of:
1. Preventative care, since diabetic neuropathy is not reversible management aims to slow
further progression and prevent complications.
a. Glycemic control
b. Foot care and daily foot inspection
c. Safety and falls - physical exercise/physiotherapy in older adults
, Pain management, 15-20% of patients have pain in the feet, burning or stabbing (small myelinated
fibers). Pain can be self-limited (½ year) or persistent.
. Antidepressants - duloxetine, venlafaxine are SNRI and amitriptyline TCA
a. Antiepileptics - gabapentin, pregabalin
b. Topical therapy - capsaicin cream (depletes substance P locally), lidocaine patches
[acupuncture, electrical nerve stimulation]
Prognosis/course: Peripheral neuropathy will affect the extremities and is classically described as a
glove and stocking anaesthesia. This poor sensation in the feet can result in complications such as
severe ulcers, infections and in severe cases the need for amputation. It can also cause muscle
weakness and loss of reflexes, especially at the ankle, leading to changes in gait. Furthermore we see
foot deformities such as hammertoes and the collapse of the mid foot. Overall prognosis depends
largely on how well the underlying condition of diabetes is handled. Treatment of diabetes may halt
progression and improve symptoms of neuropathy, however recovery is a slow process.
Guillain Barre Syndrome: (GBS) * ACUTE INFLAMMATORY DEMYELINATING polyneuropathy
Approx 2 per 100,000 people per year, depending on which source you read from. Most frequent
acute generalized polyneuropathy seen in hospitals. No gender or age preference. Caused by several
factors; after a viral or bacterial infection (VZV, mumps, CMV, mycoplasma pneumoniae, c. jejuni,
other infections). Think of gastroenteritis or URT infection in the recent history. Antibody and T cell
mediated reactions against myelin (glycoproteins). We get segmental demyelinization which in turn
could cause damage to the actual axon. This is paired with perivascular infiltration (endoneurial
vessels) with lymphocytes which ten release cytokines and cause inflammation these damage the
Schwann cell and myelin.
acute motor axonal neuropathy (AMAN) /acute inflammatory demyelinating polyneuropathy (AIDP).
Clinical symptoms are the result of the widespread inflammatory-demyelinating process in the
peripheral nerves. We get paresthesias and numbness in the toes and fingers. Over 50% get muscle
pain (hip, back and thighs). Major manifestation is muscle weakness that evolves symmetrically over
several days up to a week (ACUTE). Usually the lower extremities are first (“ascending paralysis”).
Trunk, intercostals, neck and cranial muscles may be affected later. Weakness can progress to total
motor paralysis with respiratory failure (also unreactive pupils). Other later findings are sensory loss
with vibration and propriocepsis in fingers and toes, absent reflexes, facial diplegia, systemic signs
(splenomegaly, lymphadenopathy due to viral infection), dysautonomia (tachy/bradycardia, flushing,
fluctuating hyper and hypotension, loss of sweating, urinary retention. The axonal form of GBS is
non-typical. When the axon is damaged we see abrupt and severe denervating paralysis, particularly
post infectious (c. jejuni). We can also see areflexia (rapid evolution) and muscle atrophy (early!).
Here the myelin is kinda okay but we see complement and macrophage deposits in the periaxonal
space.
What is challenging about GBS is that the variations of disease are more common than you think.
Without going too much in detail, here are some other variants and how you can distinguish from the
typical case:
1. Pharyngeal-cervical-brachial weakness, often with ptosis - Causing difficulty with swallowing,
and prox. arm weakness. DDx: myasthenia gravis (muscle weakness), diphtheria, botulism,
and a lesion affecting the central portion of the cervical cord and brainstem.
2. Fisher syndrome - triad of ataxia, areflexia, and ophthalmoplegia, without significant limb
weakness. Raises DDx: myasthenia gravis, botulism, diptheria, tick paralysis, and basilar
artery occlusion.
3. Paraparetic, ataxic, purely motor or purely sensory forms - less difficult to make the Dx.
Why? Paresthesias in the acral extremities, progressive reduction or loss of reflexes, and
relative SYMMETRY of weakness, appear after several days. Lab tests and nerve conduction
studies can confirm
