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Richard A. Lewis, M.D., Professor
Department of Neurology, Wayne State University
Introduction
Guillain Barré Syndrome (GBS) was considered for many years to be
a single disease synonymous with acute inflammatory demyelinating polyneuropathy
(AIDP). In a similar way chronic inflammatory demyelinating polyneuropathy
(CIDP) was considered to be a single entity with many similarities to AIDP
but also with clear distinctions. It is now apparent that the situation
is much more complicated and both AIDP and CIDP are part of a much broader
spectrum of disorders. As such, GBS is a true syndrome comprised of a number
of distinct entitles (Table 1)
Table 1
The Variations of Guillain-Barré Syndrome
Variations based on localization of deficits
Fisher’s Syndrome
Pharyngeal-Cervical-Brachial
Variations based on axonal or Demyelinating polyneuropathy
Acute Inflammatory Demyelinating Polyneuropathy
Acute Motor Axonal Neuropathy
Acute Motor-Sensory Axonal Neuropathy
and CIDP is also part of a larger syndrome of disorders, which for a lack of a better term we will call Chronic Immune-Mediated Demyelinating Polyneuropathy (CIMDP) (Table 2).
Table 2
Chronic Immune Mediated Demyelinating Polyneuropathy
1. Chronic Inflammatory Demyelinating Polyneuropathy
a. Classic form – motor>sensory proximal and distal
b. Sensory predominant form
c. Associated with other systemic illness
d. Associated with CNS abnormalities
e. Multifocal sensorimotor form (Lewis-Summer or MADSAM neuropathy)
2. IgM Paraprotein Associated Demyelinating Neuropathy
a. Distal Accentuated Neuropathy with or without anti-MAG (DADS
neuropathy)
b. CANOMAD
c. Others
3. Other paraprotein related disorders
a. POEMS
4. Multifocal Motor Neuropathy
a. Multifocal acquired motor axonopathy (MAMA)
This recognition of the multiple variations of these syndromes
actually helps clarify the similarities and differences between the acute
and chronic disorders.
The following will briefly outline the different acute and chronic syndromes
and point out some of the important similarities and differences.
A. Guillain-Barré Syndrome (GBS)
The most common form of GBS in the United States is AIDP which has an incidence
of 1-2/100,000 people. It is associated with rapidly evolving weakness and
areflexia. GBS can occur at any age. In many patients, there is an antecedent
infection which is usually viral. Campylobacter jejuni enteritis precedes
GBS in about 20% of patients and is the most common antecedent bacterial
infection. In addition, recent surgery is a recognized premonitory event.
Initial symptoms are usually numbness and tangling of the extremities. Aching
pain in the extremities and back is common. Subsequent weakness involving
proximal and distal muscles ensues. Usually the lower extremity muscles
are initially affected. Patents become hypo- or areflexic. Over 59% of patients
reach their nadir by 2 weeks, 80% by 3 weeks, and 90% by 4 weeks. The tempo
of progression variable and some can become flaccid and ventilator dependent
in a few days.
In addition to the ''classic'' presentation of GBS, variants have been described
Fisher syndrome with ophthalmoplegia, ataxia, and areflexia is well recognized.
In addition, other variants including Fisher syndrome plus signs of brainstem
dysfunction (Bickerstaff's Brainstem Encephalitis) and pharyngeal-cervical-brachial
weakness with ptosis (mimicking botulism) in which the weakness is confined
to the muscles of speech and swallowing, neck and shoulders has been described.
Of note is that most patients with Fisher's syndrome and some patients with
Bickerstaff's have IgG anti-ganglioside antibodies directed against GQ1b.
The pharyngeal-cervical-brachial form has an association with anti-GT1A
antibodies. These immune differences suggest that the different forms of
GBS may occur due to different immunologic reactions, most likely related
to whether the initiating infectious agent has a specific ganglioside on
its surface that cross reacts with a constituent on different nerves.
It is now recognized that GBS has both demyelinating and axonal forms. There
is an axonal form with both motor and sensory symptoms and signs, called
Acute Motor and sensational Neuropathy (AMSAN) and a pure motor axonal form,
called Acute Motor Axonal Neuropathy (AMAN). AMAN presents very similarly
to AIDP. However some differences between AMAN and AIDP have been noted
in a study comparing the two disorders. AMAN tends to progress more rapidly
and more patients are still ambulatory when the disease reaches its peak.
While patients with AMAN recover more quickly than those with AIDP more
people die with AMAN. Compared to AIDP, AMAN is much more clearly associated
with antecedent Campylobacter jejuni enteritis and the presence of IgG anti-ganglioside
antibodies, particularly to GM1 and GD1A. The association of AIDP and anti-ganglioside
antibodies is much less clear.
In virtually all forms of GBS, cerebrospinal fluid (CSF) is remarkable for
elevated protein with minimal, if any, cellular reaction. In AIDP, early
findings on nerve conduction testing include prolonged or absent measures
of proximal nerve conduction (F-waves), indicating a predilection for the
nerve roots and prolonged distal responses showing involvement of the distal
nerve terminals. Later, slowed conduction velocities and conduction block
can be demonstrated. In AMAN there can be early distal slowing but within
days the amplitudes of the responses decrease but the conduction velocities
in all segments remain relatively normal. The disorder is felt to be autoimmune
involving both the cellular and humoral mechanisms. Autopsy studies and
nerve biopsies demonstrate lymphocyte and macrophage infiltration of nerves
with demyelination in AIDP but minimal cellular reaction, preserved myelin
but macrophage infiltration of the axons at the nodes of Ranvier. Most patients
with GBS recover spontaneously, however, 10 to 20% require mechanical ventilation,
10 to 20% have residual defects, about 3% relapse, and about 3% die of the
disease. Poor prognostic indications are age over 60 and low amplitude motor
potentials on nerve conduction studies.
Plasma exchange, involving 200-250 ml of plasma per kg body weight over
7-10 days has been shown to be an effective therapy. In addition, intravenous
immunoglobulin (IVIG) has been shown to be as effective as plasma exchange.
In elderly patients with hemodynamic instability or poor venous access,
IVIG may represent the treatment of choice. Either therapy is equally effective
in shortening the length of time a patient is weak. However, the combination
of plasmapheresis and IVIG does not help more than either treatment alone.
In addition, patients and their families should not expect dramatic improvement
immediately after plasmapheresis in IVIG treatment. Corticosteroids (prednisone/methylprednisolone)
are not of benefit in the treatment of GBS.
The most important component of treatment is supportive care. Patients need
to be monitored closely for respiratory and autonomic instability. Forced
vital capacities (FVCs) need to be followed, and FVCS below 15-20 ml/kg
require endotracheal tube intubation. Progressive neck, flexor, and extensor
weakness closely correlates with respiratory compromise and can also be
used to monitor for impending respiratory failure. Leg stockings and subcutaneous
heparin 5,000 units twice daily are indicated for prevention of deep venous
thromboses and pulmonary emboli. Aggressive physical therapy is useful for
prevention of muscle contractions in a severely weak patient.
B. Chronic Inflammatory Demyelinating Polyneuropathy
(CIDP)
It is a bit more difficult, to discuss CIDP because physicians have still
not entirely agreed as to whether CIDP is a specific disease or whether
it is a syndrome with deferent forms. Most experts would use CIDP to name
a specific disease that is the major disorder within the spectrum of Chronic
Acquired Demyelinating Polyneuropathy (CADP). Some authors prefer the term
CIMDP for the syndrome.
Chronic inflammatory demyelinating polyneuropathy (CIDP) represents a significant
number of all initially undiagnosed acquired neuropathies. Diagnosis is
important because CIDP is treatable with various immunomodulating therapies.
In order to fulfill diagnostic criteria for midi weakness must be progressive
for at least 2 months which distinguishes CIDP from GBS. Weakness can vary
in severity, but is symmetric and involves proximal and distal muscles of
the upper and lower extremities. Facial and neck flexor weakness can occur.
Rarely, extraocular and respiratory muscles are involved. Sensory complaints
usually consist of numbness and tingling, but painful parenthesize are not
common. Many patients describe a loss of balance. Deep tendon reflexes are
usually absent or depressed.
A diagnosis of CIDP is supposed by showing an elevated protein in the CSF.
Nerve conduction studies are suggestive of demyelination: slowed conduction
velocities, prolonged or absent F-waves and conduction block. Sural nerve
biopsy may be helpful in excluding other etiologies such as amyloidosis,
vasculitis, and various hereditary or toxic neuropathies and may show demyelination
and occasionally inflammation. However, in many cases with a classic clinical
presentation, nerve conduction and CSF abnormalities, a nerve biopsy may
not be needed.
Randomized control trials have confirmed that prednisone, plasma exchange,
and IVIG are beneficial in CIDP. Initial therapy usually consists of prednisone
or IVIG. Prednisone is initiated with 100 mg a day as a one-time dose in
the morning. Once improvement begins, usually within 2-4 weeks, it can be
switched to alternate day therapy. When the strength has returned to normal
or improvement has plateaued (usually within 3-6 months), the prednisone
is slowly tapered. A few patients can eventually be tapered completely off
the prednisone, however, many patients relapse. IVIG is stated at 2 gm/kg
over 2-5 days, and is followed by monthly maintenance doses of 0.4 to 1
gm/kg. The length of time of maintenance infusions varies from patient to
patient. It is important for both the patients and physician to realize
CIDP is a chronic disorder and may require immunosuppressive therapy for
many years. When patients do not respond adequately to prednisone or IVIG,
plasmapheresis is often initiated. In addition, azathioprine and cyclosporine
can be used as a second line immunosuppressive drug. Occasionally, high-dose
intravenous methylprednisolone (''pulse'' corticosteroids) may be helpful.
There are some variants that are still considered CIDP. These include a
sensory form in which patients aren't weak only have sensory symptoms and
signs but the nerve condition studies show slowing of motor nerves as seen
in the more ''classic'' form of CIDP. CIDP associated with other medical
illnesses is also called CIDP.
There are other disorders within the syndrome of CIMDP that are not called
CIDP because the clinical picture and response to treatment are different.
Patients with demyelinating neuropathies who have an 1gM paraprotein do
not typically respond to plasmapheresis, IVIG or corticosteroids. The patients
usually have more sensory symptoms than those with midi and both the clinical
findings and the nerve condition changes tend to be very distal. This chronic
Demyelinating neuropathy has also been called Distal Acquired Demyelinating
Symmetric Neuropathy - or DADS - distinguishing it from classic CIDP. Over
50% of these patients have anti-bodies against Myelin-Associated-Glycoprotein
(MAG). No treatment has been clearly effusive but recent reports have been
encouraging regarding the use of a monoclonal antibody directed against
B-lymphocytes (Rituximab).
Other forms of CIMDP have also been described in which the multifocal nature
of the disease is striking.
C. Multifocal Demyelinating Neuropathy - Pure motor
and Motor-sensory Forms
A group of predominantly male patients between 20 and 40 years of age with
multifocal demyelinating motor neuropathy can develop a neuropathy resembling
the lower motor neuron form of motor neuron disease. This is called multifocal
motor neuropathy or MMN. MMN is not considered a form of CIDP because of
its distinctive clinical picture, the immunologic findings and the specific
treatments that have been found to be effective. Initially, there is weakness
of one hand which is slowly progressive over months or years, spreading
asymmetrically to the other hand and feet. Some patients have vague sensory
symptoms, but the sensory examination is usually normal. On electrophyslologic
testing, these patients usually have focal conduction block, temporal dispersion
and slowing in multiple motor nerves with normal sensory studies. Sensory
nerve biopsy is often normal. The presence of IgM antibodies to GM 1 ganglioside
have been demonstrated in some, but not all, patients with multi-focal conduction
block. The significance of ganglioside antibodies in these patients is still
not known. Therapy with IVIG monthly may be beneficial as the treatment
doses are the same as in CIDP. If IVIG is not effective, aggressive immunosuppressive
therapy can be tried with intravenous cyclophosphamide. Prednisone alone
has generally been ineffective and may make the disease worse and plasmapheresis
has also not been very effective. Rituximab has also been reported to be
effective but more studies are needed before this can be recommended.
There is also a form of multifocal demyelinating neuropathy that has both
prominent motor and sensory symptoms and signs. This was first described
by Drs. Lewis, Sumner, Brown and Asbury and is known both as the ''Lewis-Sumner
Syndrome'' and MADSAM neuropathy (Multifocal Acquired Demyelinating Sensory
and Motor). Treatment is similar to CIDP with either prednisone or IVIG
as initial therapy choices. As opposed to AMAN, no specific antibodies have
been detected and the treatment response is virtually identical to CIDP
and as such, the disorder is considered a variant of CIDP. Finally, there
may be a chronic pure motoraxonal neuropathy resembling MMN which has been
called Multifocal Motor Axonopathy or MAMA. Some of these patients may respond
to IVIG therapy
The Relationship of GBS and CIDP
There are a number of features of these disorders that point to a strong
relationship between the acute disorders (GBS) and chronic disorders (CIMDP).
There is a temporal pattern of disease that we arbitrarily use to distinguish
these disorders, but there is clearly a continuum that suggests a relationship.
Most authorities consider GBS if the disease progression is under 4 weeks
and CIDP or variant if the disease progresses for over 8 weeks. Those patients
with a progression between 4 and 8 weeks have been called SIDP (Subacute)
but the response to treatment is similar to that of CIDP. It is most likely
that GBS is an acute monophasic illness in which the immune response is
under 4 weeks. Any longer progression is more likely to be a chronic illness
with a different immune reactions. Consistent with this is that the antibodies
seen with GBS have been associated with IgG immunoglobulins while the chronic
disorders have been associated with 1gM antibodies.
Some of the acute disorders have a corresponding chronic disorder. For instance
AMAN and MMN have features in common. Both are pure motor disorders with
an association with antiGM1 antibodies The clinical features of Fisher's
syndrome have similarities to a recently described chronic disorder called
CANOMAD and both have antibodies against GQ1b. Both AIDP and CIDP; both
symmetric proximal and distal disorders with more motor than sensory abnormalities
have not been found to have specific antibody abnormalities and may have
more cell mediated immune aspects than the axonal disorders.
However differences are also apparent between the acute and chronic disorders.
Besides the immunoglobulin difference mentioned above, the acute disorders
have tended not to respond to corticosteroids while many of the chronic
disorders respond. The acute disorders have a much stronger association
with an antecedent event, most commonly an infection, and involvement of
the autonomic nervous system and cranial nerves. Pain is very common in
GBS; it occurs less often in CIMDP. The chronic disorders rarely have a
recognized antecedent event. In addition, the acute disorders clearly have
both demyelinating and axonal forms, while the chronic syndrome does not
have well described axonal variants. Finally, even without therapy patients
with the acute disorders eventually improve, although recovery is faster
with treatment. However, the chronic demyelinating neuropathies do not spontaneously
improve without treatment.
It is worthwhile to mention that a GBS patient who has residual numbness,
weakness, and fatigue, or incomplete recovery, should not be classified
as having CIDP. Some residual symptoms are common in GBS patients, and they
do not require that a patient remain on chronic IVIG, prednisone, plasmapheresis,
or other immune modulating therapy. Another important point is that not
all new symptoms that occur in a patient necessarily mean that the new complaints
are due to GBS or CIDP. For example, a patient could have recovered completely
from GBS and five years later could develop numbness of the feet again,
but now the cause is a newly diagnosed disorder such as diabetes mellitus
or vitamin B12 deficiency. So, it is very important for patients and their
physicians to consider other possible causes for new neurologic symptoms
other than
GBS and CIDP.
In summary, there is a close relationship between GBS and CIMDP. Both are
true syndromes in that they comprise a number of different distend disorders.
The similarities and differences between the acute and chronic disorders
teach us about how the immune system reaction can vary. It also provides
a framework to study different treatments.
References provided upon request.