**2. IVIg in therapy of autoimmune neuropathies**

Currently CIDP, GBS and MMN are the three major immune neuropathies, in which the latest evidence strongly supports the use of IVIg as a first-line therapy (level A recommendation). However, questions remain regarding the dose, timing and duration of IVIg treatment in these disorders. The efficacy of IVIg has been also proven in some paraneoplastic neuropathies (level B) (European Federation of Neurology Society [EFNS] task force, 2008; Elovaara & Hietaharju, 2010). There are other peripheral neuropathies in which there are reports of the efficacy of IVIg. These include diabetic amyotrophy, vasculitic peripheral neuropathy and painful sensory neuropathy associated with Sjogren's syndrome. The evidence for these conditions has been insufficient to earn a recommendation for the use of IVIg from national or international guidelines (Hughes et al, 2009).

#### **2.1 Guillan-barre syndrome (GBS)**

GBS is an autoimmune disorder of the peripheral nervous system. The incidence of GBS is approximately two per 100 000/year in adults. It may lead to respiratory failure requiring

Intravenous Immunoglobulins in Neurological Diseases: Established and Novel Clinical Applications 339


CIDP is a progressive or relapsing autoimmune disease that targets the myelin sheaths of the peripheral nerves, leading to weakness, sensory loss and impairment of gait and coordination. It has a variable clinical course causing both temporary and permanent disability. There is no definitive test for CIDP, and in most patients diagnosis is based on the clinical presentation and demonstration of demyelinating abnormalities in electrodiagnostic

It has been shown to respond to several therapies, including corticosteroids, PE and IVIg. The efficacy of IVIg has been assessed in five RCTs including 235 participants. In addition, there is one RCT, which has compared IVIg with PE, and one study, which has compared IVIg with prednisolone. A recently published Cochrane review summarizes the results of these studies and concludes that IVIg therapy improves disability for at least 2–6 weeks compared with placebo (Eftimov et al., 2009). During this induction period IVIg has an

The ICE study (Hughes et al, 2008) that is included in this review is not only the largest but also the longest reported RCT ever performed in CIDP patients. Furthermore, it was the first trial aimed to assess the long-term efficacy of IVIg. The results of ICE study unequivocally

The initial dose used in the ICE study (2 g/kg) was similar to that used in practice. This dose was shown to be more effective than 1 g/kg or 0·25 g/kg, although higher doses were not examined. The initial dose is usually given over one or several days, depending on tolerability or convenience. Patients who do not respond to an initial dose may respond to subsequent doses. In the ICE study, 44% of responders improved by 3weeks after the initial treatment, and an additional 50% of patients responded only after a second dose of 1 g/kg at week 3, as measured at week 6 of the study. However, it is not known whether even more patients would have improved if additional treatments had been given, as patients who did not show improvement, including those who were stable, were crossed-over at week 6. In clinical practice, initial responses have been seen up to 3 months into the treatment, and stabilization of previously progressive disease is considered to be a positive response

IVIg responsive patients in the ICE trial were treated with 1 g/kg every 3 weeks for up to 24 weeks, with the responsive patients re-randomized to continue treatment or placebo in phase 2 of the study for an additional 24 weeks. Continued improvement was observed in some patients at up to 32 weeks into the study. Approximately 50% of the responders in the first phase of the study suffered a relapse during phase 2 when switched to placebo. Given the goal of achieving maximal improvement, a reasonable strategy would be to continue treatment until the improvement plateaus, before stopping to see whether additional treatments are still needed. Discontinuing the treatments prior to that point would risk

demonstrated a beneficial effect on disability that is sustained up to 48 weeks.


with a second course of IVIg (good practice point).

studies (Hughes et al, 2009).

(Hughes et al, 2009).

efficacy similar to PE and corticosteroids.

leaving the patient with less than optimal function.

**2.2 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)** 

artificial ventilation in up to 30% of patients and about 5% die in this disease (Hughes et al, 2006).

GBS consists of four major subtypes: acute inflammatory demyelinating polyneuropathy (AIDP); acute motor axonal neuropathy (AMAN); acute motor and sensory axonal neuropathy (AMSAN); and Fisher syndrome. The subtypes can be differentiated by clinical, electrophysiological and pathological findings. Diagnosis of GBS is made in the setting of the classic clinical scenario of a monophasic illness reaching a nadir within 4 weeks with symmetric weakness and sensory loss, areflexia and elevated cerebrospinal fluid (CSF) protein without pleocytosis. Presumed antecedent inciting events, such as infections, occur in up to 80% (van Doorn P.A. et al, 2008).

Molecular mimicry probably plays an important role in the pathogenesis. Infection with a pathological agent such as *Campylobacter jejuni* leads to the formation of cross-reacting antibodies. In AIDP, such cross-reacting anti-myelin or anti-ganglioside antibodies attack Schwann cell surface epitopes of motor and sensory fibres. Subsequent complement activation and macrophage infiltration leads to multi-focal inflammatory demyelination with conduction failure and secondary axonal degeneration. AMAN and AMSAN are characterized by axonal/nodal antibody binding, complement activation, macrophage attachment at nodes, opening of the periaxonal space and macrophage infiltration in motor axons in AMAN, or in motor and sensory axons in AMSAN (van Doorn P.A. et al, 2008).

The proposed autoimmune aetiology led to the introduction of immunotherapy. Before its introduction, 10% of patients died and 20% were left seriously disabled (EFNS task force, 2008). Plasma exchange (PE) was the first treatment of GBS that was shown to offer a significant benefit in randomized controlled trials (RCT) and became. The first RCT on the use of IVIg was published in 1992, followed later by other trials.

Even though both IVIG and PE are considered as first-line therapy for GBS, IVIG is usually favored over PE due to its simplicity and better availability. Standard therapy of IVIG is 0.4 g kg given for 5 days, but there is only limited evidence concerning the optimal dosage. There are also other unanswered questions. Additional primary treatments are needed, as up to 20% of patients with GBS die or are unable to walk after 1 year. Treatments to enhance nerve regeneration and to improve function in existing but partially repaired nerves are also required. The Inflammatory Neuropathy Consortium of the Peripheral Nerve Society defined a need for trials of IVIg treatment in mild GBS and Fisher syndrome, an IVIg dosefinding study in GBS and studies on the use of complement inhibitors and sodium channel blockers (Hughes et al, 2009).The most urgent question is whether patients who continue to deteriorate after a standard course of IVIG should receive a second course or receive some other additional treatment An international study concerning this last issue is about to be launched in the near future (Elovaara & Hietaharju, 2010).

Recommendations:




#### **2.2 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)**

338 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

artificial ventilation in up to 30% of patients and about 5% die in this disease (Hughes et al,

GBS consists of four major subtypes: acute inflammatory demyelinating polyneuropathy (AIDP); acute motor axonal neuropathy (AMAN); acute motor and sensory axonal neuropathy (AMSAN); and Fisher syndrome. The subtypes can be differentiated by clinical, electrophysiological and pathological findings. Diagnosis of GBS is made in the setting of the classic clinical scenario of a monophasic illness reaching a nadir within 4 weeks with symmetric weakness and sensory loss, areflexia and elevated cerebrospinal fluid (CSF) protein without pleocytosis. Presumed antecedent inciting events, such as infections, occur

Molecular mimicry probably plays an important role in the pathogenesis. Infection with a pathological agent such as *Campylobacter jejuni* leads to the formation of cross-reacting antibodies. In AIDP, such cross-reacting anti-myelin or anti-ganglioside antibodies attack Schwann cell surface epitopes of motor and sensory fibres. Subsequent complement activation and macrophage infiltration leads to multi-focal inflammatory demyelination with conduction failure and secondary axonal degeneration. AMAN and AMSAN are characterized by axonal/nodal antibody binding, complement activation, macrophage attachment at nodes, opening of the periaxonal space and macrophage infiltration in motor axons in AMAN, or in motor and sensory axons in AMSAN (van Doorn P.A. et al, 2008). The proposed autoimmune aetiology led to the introduction of immunotherapy. Before its introduction, 10% of patients died and 20% were left seriously disabled (EFNS task force, 2008). Plasma exchange (PE) was the first treatment of GBS that was shown to offer a significant benefit in randomized controlled trials (RCT) and became. The first RCT on the

Even though both IVIG and PE are considered as first-line therapy for GBS, IVIG is usually favored over PE due to its simplicity and better availability. Standard therapy of IVIG is 0.4 g kg given for 5 days, but there is only limited evidence concerning the optimal dosage. There are also other unanswered questions. Additional primary treatments are needed, as up to 20% of patients with GBS die or are unable to walk after 1 year. Treatments to enhance nerve regeneration and to improve function in existing but partially repaired nerves are also required. The Inflammatory Neuropathy Consortium of the Peripheral Nerve Society defined a need for trials of IVIg treatment in mild GBS and Fisher syndrome, an IVIg dosefinding study in GBS and studies on the use of complement inhibitors and sodium channel blockers (Hughes et al, 2009).The most urgent question is whether patients who continue to deteriorate after a standard course of IVIG should receive a second course or receive some other additional treatment An international study concerning this last issue is about to be





2006).

in up to 80% (van Doorn P.A. et al, 2008).

use of IVIg was published in 1992, followed later by other trials.

launched in the near future (Elovaara & Hietaharju, 2010).

extra benefit and can not be recommended (level B).

considered to be equally effective (level A).

shortterm benefit (level C).

treatment (level C).

Recommendations:

CIDP is a progressive or relapsing autoimmune disease that targets the myelin sheaths of the peripheral nerves, leading to weakness, sensory loss and impairment of gait and coordination. It has a variable clinical course causing both temporary and permanent disability. There is no definitive test for CIDP, and in most patients diagnosis is based on the clinical presentation and demonstration of demyelinating abnormalities in electrodiagnostic studies (Hughes et al, 2009).

It has been shown to respond to several therapies, including corticosteroids, PE and IVIg. The efficacy of IVIg has been assessed in five RCTs including 235 participants. In addition, there is one RCT, which has compared IVIg with PE, and one study, which has compared IVIg with prednisolone. A recently published Cochrane review summarizes the results of these studies and concludes that IVIg therapy improves disability for at least 2–6 weeks compared with placebo (Eftimov et al., 2009). During this induction period IVIg has an efficacy similar to PE and corticosteroids.

The ICE study (Hughes et al, 2008) that is included in this review is not only the largest but also the longest reported RCT ever performed in CIDP patients. Furthermore, it was the first trial aimed to assess the long-term efficacy of IVIg. The results of ICE study unequivocally demonstrated a beneficial effect on disability that is sustained up to 48 weeks.

The initial dose used in the ICE study (2 g/kg) was similar to that used in practice. This dose was shown to be more effective than 1 g/kg or 0·25 g/kg, although higher doses were not examined. The initial dose is usually given over one or several days, depending on tolerability or convenience. Patients who do not respond to an initial dose may respond to subsequent doses. In the ICE study, 44% of responders improved by 3weeks after the initial

treatment, and an additional 50% of patients responded only after a second dose of 1 g/kg at week 3, as measured at week 6 of the study. However, it is not known whether even more patients would have improved if additional treatments had been given, as patients who did not show improvement, including those who were stable, were crossed-over at week 6. In clinical practice, initial responses have been seen up to 3 months into the treatment, and stabilization of previously progressive disease is considered to be a positive response (Hughes et al, 2009).

IVIg responsive patients in the ICE trial were treated with 1 g/kg every 3 weeks for up to 24 weeks, with the responsive patients re-randomized to continue treatment or placebo in phase 2 of the study for an additional 24 weeks. Continued improvement was observed in some patients at up to 32 weeks into the study. Approximately 50% of the responders in the first phase of the study suffered a relapse during phase 2 when switched to placebo. Given the goal of achieving maximal improvement, a reasonable strategy would be to continue treatment until the improvement plateaus, before stopping to see whether additional treatments are still needed. Discontinuing the treatments prior to that point would risk leaving the patient with less than optimal function.

Intravenous Immunoglobulins in Neurological Diseases: Established and Novel Clinical Applications 341

There is only one RCT on the use of an immunosuppressive agent as an additional therapy (Piepers et al, 2007). This study with 28 patients showed that mycophenolate mofetil neither

Elevated anti-ganglioside GM1 antibodies and definite conduction block have been shown to be correlated with a favourable response to IVIg (class IV evidence) (EFNS task force, 2008). However, in one retrospective study, treatment with higher than normal maintenance doses of IVIg (1.6–2.0 g/kg given over 4–5 days) promoted re-innervation, decreased the number of conduction blocks and prevented axonal degeneration in 10 MMN patients for





Paraproteinaemia, also known as monoclonal gammopathy, is characterized by the presence of abnormal immunoglobulin (M protein) produced by bone marrow cells in blood. The different types of immunoglobulin are classified according to the heavy chain class as IgG, IgA or IgM. The non-malignant paraproteinaemias are generally referred to as monoclonal

Paraproteins are found in up to 10% of patients with peripheral neuropathy which is not secondary to another primary illness. In about 60% of patients with MGUS-related neuropathy the paraprotein belongs to the IgM subclass. In almost 50% of patients who have IgM MGUS and a peripheral neuropathy, the M protein reacts against myelin-associated glycoprotein. The most common type of IgM MGUS related peripheral nerve involvement is a distal, symmetrical demyelinating neuropathy. Patients with IgG or IgA paraproteinaemic neuropathy usually have both proximal and distal weakness and sensory impairment that is

Two RCTs with IVIg have been performed, encompassing 33 patients with IgM paraproteinaemic demyelinating neuropathy (class II). A third randomized study was an open parallel group trial with 20 patients which compared IVIg and recombinant interferona (class II). The results of these three trials have been summarized in a Cochrane review, which concluded that IVIg is relatively safe and may produce some short-term benefit

No RCTs are available on the effects of IVIg in IgG or IgA paraproteinaemic neuropathy. There is one retrospective review of 20 patients with IgG MGUS neuropathy treated with IVIg; beneficial response was found in eight of them (class IV). An open prospective trial of IVIg reported clinical improvement in two of four patients with IgG MGUS (class IV). In a review which included 124 patients with IgG MGUS neuropathy, 81% of the 67 patients with a predominantly demyelinating neuropathy responded to the same immunotherapies

produced significant benefit nor reduced the need for IVIg.

g/kg in 2–5 days) as a first-line treatment (level A).

**2.4 Paraproteinaemic demyelinating neuropathy** 

gammopathy of undetermined significance (MGUS).

indistinguishable from CIDP.

(Lunn & Nobile-Orazio, 2006).

every 4–8 weeks (good practice point) (EFNS task force, 2008).

up to 12 years (Vucic et al, 2004).

Recommendations:

C).

point).

CIDP patients with very mild symptoms may not need any treatment at all. Approximately 20% of the CIDP patients seem to improve spontaneously. Treatment should be considered for patients with moderate or severe disability. IVIg (2 g kg in 2–5 days) or corticosteroids (1 mg kg or 60 mg daily) are recommended as first-line treatment in sensory and motor CIDP (EFNS task force, 2008). For pure motor CIDP, IVIg treatment should be the first choice and if corticosteroids are used, patients should be monitored closely for deterioration. In patients with relapsing–remitting CIDP responding to IVIg, attempts should be made to reduce the dose in order to find out if the patient still needs IVIg and what is the adequate dose. In addition to IVIg, PE can be considered as a treatment of choice in long-term therapy of relapsing–remitting CIDP. A number of immunosuppressant and chemotherapeutic agents have been reported to be effective in open studies, but only azathioprine and interferon beta have been investigated in RCT, with negative results (Hughes et al, 2004).

CIDP is a treatable disease whose manifestations can be prevented by early diagnosis and treatment with IVIg. Additional efforts are needed, however, to develop more reliable diagnostic tests, establish optimal treatment regimens and increase awareness of this condition.

Recommendations:


#### **2.3 Multifocal motor neuropathy (MMN)**

MMN is a rare autoimmune disorder which may cause prolonged periods of disability due to progressive weakness of one or more limbs.

There are four RCTs, which have examined the effects of IVIg vs placebo in patients with MMN. The total number of participants in these trials was only 34. A Cochrane review, however, showed that muscle strength improved in 78% of patients treated with IVIg and only in 4% of those who received placebo (van Schaik et al, 2005).

Because both prednisolone and PE have proved to be ineffective and even harmful, and cyclophosphamide, even though moderately effective, has significant side effects in longterm use, IVIg remains the only beneficial treatment for MMN.

Approximately one third of patients with MMN have a sustained remission (>12 months) with IVIg alone and approximately half of the patients need repeated IVIg infusions (Leger et al, 2008). The effect of IVIg declines during prolonged treatment, even if the dosage is increased, probably due to ongoing axonal degeneration (Terenghi et al, 2004).

There is only one RCT on the use of an immunosuppressive agent as an additional therapy (Piepers et al, 2007). This study with 28 patients showed that mycophenolate mofetil neither produced significant benefit nor reduced the need for IVIg.

Elevated anti-ganglioside GM1 antibodies and definite conduction block have been shown to be correlated with a favourable response to IVIg (class IV evidence) (EFNS task force, 2008). However, in one retrospective study, treatment with higher than normal maintenance doses of IVIg (1.6–2.0 g/kg given over 4–5 days) promoted re-innervation, decreased the number of conduction blocks and prevented axonal degeneration in 10 MMN patients for up to 12 years (Vucic et al, 2004).

Recommendations:

340 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

CIDP patients with very mild symptoms may not need any treatment at all. Approximately 20% of the CIDP patients seem to improve spontaneously. Treatment should be considered for patients with moderate or severe disability. IVIg (2 g kg in 2–5 days) or corticosteroids (1 mg kg or 60 mg daily) are recommended as first-line treatment in sensory and motor CIDP (EFNS task force, 2008). For pure motor CIDP, IVIg treatment should be the first choice and if corticosteroids are used, patients should be monitored closely for deterioration. In patients with relapsing–remitting CIDP responding to IVIg, attempts should be made to reduce the dose in order to find out if the patient still needs IVIg and what is the adequate dose. In addition to IVIg, PE can be considered as a treatment of choice in long-term therapy of relapsing–remitting CIDP. A number of immunosuppressant and chemotherapeutic agents have been reported to be effective in open studies, but only azathioprine and interferon beta have been investigated in RCT, with negative results (Hughes et al, 2004). CIDP is a treatable disease whose manifestations can be prevented by early diagnosis and treatment with IVIg. Additional efforts are needed, however, to develop more reliable diagnostic tests, establish optimal treatment regimens and increase awareness of this




MMN is a rare autoimmune disorder which may cause prolonged periods of disability due

There are four RCTs, which have examined the effects of IVIg vs placebo in patients with MMN. The total number of participants in these trials was only 34. A Cochrane review, however, showed that muscle strength improved in 78% of patients treated with IVIg and

Because both prednisolone and PE have proved to be ineffective and even harmful, and cyclophosphamide, even though moderately effective, has significant side effects in long-

Approximately one third of patients with MMN have a sustained remission (>12 months) with IVIg alone and approximately half of the patients need repeated IVIg infusions (Leger et al, 2008). The effect of IVIg declines during prolonged treatment, even if the dosage is

increased, probably due to ongoing axonal degeneration (Terenghi et al, 2004).

of daily living may be monitored without treatment (good practice point). - Treatment should be considered for patients with moderate or severe disability.

condition.

Recommendations:

point).

**2.3 Multifocal motor neuropathy (MMN)** 

to progressive weakness of one or more limbs.

only in 4% of those who received placebo (van Schaik et al, 2005).

term use, IVIg remains the only beneficial treatment for MMN.


#### **2.4 Paraproteinaemic demyelinating neuropathy**

Paraproteinaemia, also known as monoclonal gammopathy, is characterized by the presence of abnormal immunoglobulin (M protein) produced by bone marrow cells in blood. The different types of immunoglobulin are classified according to the heavy chain class as IgG, IgA or IgM. The non-malignant paraproteinaemias are generally referred to as monoclonal gammopathy of undetermined significance (MGUS).

Paraproteins are found in up to 10% of patients with peripheral neuropathy which is not secondary to another primary illness. In about 60% of patients with MGUS-related neuropathy the paraprotein belongs to the IgM subclass. In almost 50% of patients who have IgM MGUS and a peripheral neuropathy, the M protein reacts against myelin-associated glycoprotein. The most common type of IgM MGUS related peripheral nerve involvement is a distal, symmetrical demyelinating neuropathy. Patients with IgG or IgA paraproteinaemic neuropathy usually have both proximal and distal weakness and sensory impairment that is indistinguishable from CIDP.

Two RCTs with IVIg have been performed, encompassing 33 patients with IgM paraproteinaemic demyelinating neuropathy (class II). A third randomized study was an open parallel group trial with 20 patients which compared IVIg and recombinant interferona (class II). The results of these three trials have been summarized in a Cochrane review, which concluded that IVIg is relatively safe and may produce some short-term benefit (Lunn & Nobile-Orazio, 2006).

No RCTs are available on the effects of IVIg in IgG or IgA paraproteinaemic neuropathy. There is one retrospective review of 20 patients with IgG MGUS neuropathy treated with IVIg; beneficial response was found in eight of them (class IV). An open prospective trial of IVIg reported clinical improvement in two of four patients with IgG MGUS (class IV). In a review which included 124 patients with IgG MGUS neuropathy, 81% of the 67 patients with a predominantly demyelinating neuropathy responded to the same immunotherapies

Intravenous Immunoglobulins in Neurological Diseases: Established and Novel Clinical Applications 343

neuropathy and radiculoneuropathy, based on the predominant neuropathic symptoms. The majority of patients are diagnosed with Sjogren's syndrome after neuropathic symptoms appearance. Painful sensory neuropathy without sensory ataxia is the second more frequent form of neuropathy associated with Sjogren's syndrome. It is characterised by chronic progression of sensory symptoms without substantial motor involvement, although the affected sensory modalities and distribution pattern vary. Autonomic symptoms, like abnormal pupils and orthostatic hypotension are often seen. Unelicited somatosensory evoked potentials and spinal cord posterior column abnormalities in MRI are observed. Sural nerve biopsy specimens reveal variable degrees of axon loss, predominantly small fibre loss (Mori et al, 2005). Patients usually suffer from severe neuropathic pain, with small-fiber neuropathy causing lancinating or burning pain which can disproportionately affect the proximal torso or extremities, and the face (ie, in a "non-

There are reports and small open studies of the efficacy of IVIg in painful sensory


Myasthenia gravis (MG) is caused by autoantibodies against antigen in the post-synaptic neuromuscular membrane; in most patients against the acetylcholine receptor (AChR), in 5% against muscle-specific tyrosin kinase (MuSK), and in 5% against undefined antigen. A

The efficacy of IVIg in the treatment of MG has been confirmed by five controlled, prospective studies that are summarized in a Cochrane review. In acute exacerbations of MG, IVIG and PE have roughly the same efficacy, but when using IVIg the effect is slightly

The optimal dose of IVIG in MG has also been debated. So far no marked superiority of IVIg 2 g kg over 2 days compared to 1 g kg in a single day has been detected. The dose used has mostly been 2 g kg resulting in the improvement after 3–6 days. Although IVIg is an effective treatment for acute exacerbations of MG, it is not recommended as maintenance therapy. Importantly, IVIg is often used in preparing MG patients for thymectomy or other types of surgery in case they have severe weakness, bulbar symptoms, poor pulmonary function, or a thymoma, even though there are no controlled studies justifying this practice. IVIg therapy has also been considered as rescue therapy in worsening MG, exacerbations of the disease during pregnancy and before giving birth, and neonatal MG. IVIg is considered




length-dependent distribution") (Birnbaum, 2010).

**3. IVIg in therapy of myasthenia gravis (MG)** 

slower and there are less side effects (Gajdos et al, 2006).

safe in children and in elderly patients (EFNS task force, 2008).

and for short-term treatment of severe MG (level A).


complicating disorders.

Recommendations:

use of IVIg.

Recommendations

neuropathy associated with Sjogren's syndrome (Hughes et al, 2009).

direct induction of muscle weakness by the autoantibodies has been shown.

used for CIDP (including IVIg) as compared with 20% of those with axonal neuropathy (class IV). A Cochrane review states that observational or open trial data provides limited support for the use of immunotherapy, including IVIg, in patients with IgG and IgA paraproteinaemic neuropathy (Allen et al, 2007).

Recommendations:

