**5. IVIg in therapy of demyelinating diseases of central nervous system**

#### **5.1 Multiple sclerosis (MS)**

Multiple sclerosis (MS) is a central nervous system chronic inflammatory disease that is characterized by an extensive and complex immune response. It is the most common demyelinating disease of the central nervous system in young adults. MS can cause a variety of symptoms**,** including changes in sensation, visual problems, muscle weakness, depression**,** difficulties with coordination and speech, severe fatigue, cognitive impairment, problems with balance, overheating, and pain**.** MS will cause impaired mobility and disability in more severe cases. Multiple sclerosis may take several different forms, with new symptoms occurring either in discrete attacks or slowly accruing over time. Between attacks, symptoms may resolve completely, but permanent neurologic problems often persist, especially as the disease advances. MS currently does not have a cure, though several treatments are available that may slow the appearance of new symptoms (Baumstarck-Barrau et al, 2011)

Although earlier trials on the efficacy of IVIg in Relapsing Remitting MS (RRMS) have demonstrated a reduction in relapses, a recent study investigating the prevention of relapses with IVIg (PRIVIG trial) failed to confirm these earlier observations (Fazekas et al, 2008). In this study 127 patients with RRMS participated in a double blind, placebo-controlled trial, in which 44 and 42 patients received treatment with 0.2 or 0.4 g kg of IVIg and 42 patients received placebo every 4 weeks for 48 weeks. After 1 year, the proportion of relapse-free patients did not differ between the groups, and there was no difference in MRI activity assessed 6-weekly. The authors of the study suggested that the obtained results may be related to short disease duration and overall disease activity of the study population that was more like that observed in a population with a clinically isolated syndrome.

The efficacy of IVIg in the treatment of MS exacerbations has been addressed in small addon type studies that could not demonstrate any additional benefits due to addition of IVIg to conventional treatment of acute exacerbations with high-dose IV methylprednisolone. However, a recent study reported that IVIg might have a beneficial effect in patients with insufficient recovery from optic neuritis, if treatment with high-dose IV methylprednisolone fails (Achiron, 2008). No clinically significant effects were seen in progressive forms of MS, and consequently IVIg is not recommended in these conditions (Elovaara et al, 2010).

Currently the main indication for the use of IVIg in MS is to reduce relapses during pregnancy or breastfeeding when other therapies may not be used safely (Haas & Homes, 2007).

Recommendations:

Intravenous Immunoglobulins in Neurological Diseases: Established and Novel Clinical Applications 347

Lambert-Eaton myasthenic syndrome (LEMS) is an immune-mediated disorder of the presynaptic neuromuscular transmission, which more frequently occurs as the remote effect of a neoplasm. The clinical features described are proximal weakness, especially in the lower limbs, with diminished tendon reflexes and post-tetanic potentiation. Autonomic symptoms are often reported, including pupil abnormalities, dry eyes and mouth, and erectile

LEMS is considered to respond best to immunosupressive treatment. However, there is only one report showing the beneficial but short-term effect of IVIg on the muscle strength in LEMS (class II evidence) and there is also a recent Cochrane review that has concluded that limited data from one placebo-controlled study show improvement in muscle strength after

The IVIg response regarding improvement of muscle strength does probably not differ in

Acquired neuromyotonia is a condition associated with muscle hyperactivity that includes muscle stiffness, cramps, myokymia, pseudomyotonia and weakness, most common in the limbs and trunk. The typical finding on electromyography is spontaneous motor unit discharges occurring in distinctive doublets, triplets, or longer runs with high intraburst

Only one case report describes the beneficial effect of IVIg in patient with neuromyotonia, whilst another case report demonstrated worsening after IVIG therapy (EFNS task force,

Opsoclonus refers to involuntary, conjugate, multivectorial, saccadic eye movements. It can occur as an isolated neurologic anomaly but, when it occurs with involuntary multifocal jerking movements of the skeletal musculature, the phenomenon is known as opsoclonus– myoclonus syndrome (OMS). The syndrome often includes features of ataxia, or incoordination with voluntary movements. In the setting of malignancy, opsoclonus is linked most clearly to neuroblastoma, occurring in 3% of childhood cases. Anti-neuronal antibodies, usually to nuclear antigens, are considered markers of immune system

Symptoms in paraneoplastic opsoclonus - ataxia syndrome in paediatric neuroblastoma patients are stated to improve, although data concerning the long-term benefits of the treatment is lacking (class IV evidence). In adult patients the response is less immunosuppressive, although IVIg is suggested to accelerate recovery (class IV evidence)


Cerebellar dysfunction is one of the most common paraneoplastic presentations of cancer. The tumours more commonly involved are small-cell lung cancer, gynaecological and breast

activation in this disorder, detected in 81% of pediatric patients (Pittock et al, 2003).


**6.1 Lambert – eaton myasthenic syndrome (LEMS)** 

dysfunction (Maddison & Newsom-Davis, 2005).

IVIg (Maddison & Newsom-Davis, 2005).

Recommendations:

**6.2 Neuromyotonia** 

2008).

frequency (Hart et al, 2002).

(EFNS task force, 2008). Recommedation:

patients (good practice point).

**6.4 Paraneoplastic cerebellar degeneration** 

paraneoplastic and non-paraneoplastic LEMS.

**6.3 Paraneoplastic opsoclonus ataxia syndrome (OMS)** 


### **5.2 Neuromyelitis optica (NMO)**

Neuromyelitis optica (NMO) termed also Devic's disease, is a demyelinating disease of the spinal cord and optic nerves that may manifest by recurrent attacks and tends to have a poor prognosis.

There is only one case type study suggesting that monthly IVIg was associated with cessation of relapses (class IV evidence) (Bakker & Metz, 2004).

#### **5.3 Balo's concentric sclerosis**

Balo's concentric sclerosis is a severe demyelinating disease with poor prognosis. There is a case report suggesting that IVIg (0.4 g/kg/daily for 5 days) and interferon-beta-1a given post-partum may result partial neurological improvement (class IV evidence) (Airas et al, 2005).

#### **5.4 Acute disseminated encephalomyelitis (ADEM)**

Acute-disseminated encephalomyelitis (ADEM) is a monophasic immune-mediated demyelinating disease of the central nervous system that is associated with significant morbidity and mortality. Controlled studies on therapy in ADEM are not available. Standard treatment is high-dose steroids. The use of IVIg (0.4 g/kg/day for 5 days or 1 g/kg/2 days) has been reported in case reports and small series suggesting that IVIg may have favourable effects when used as an initial therapy in both adults and children (class IV evidence). IVIg may have beneficial effects also as second line therapy (class IV evidence) [149–152] especially in patients who could not receive or failed to respond to steroids (class IV evidence) or in patients with peripheral nervous system involvement and steroid failure (class IV evidence). Alternatively combination therapy by steroids and IVIG (class IV evidence) or steroids, IVIg and PE were suggested to have favourable effects especially if given early in the course of disease (class IV evidence) (EFNS task force 2008).

Recommendations:

