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.