**12. Conclusion**

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

Standard treatment of RE consists of anti-epileptic drugs, high-dose steroids or PE. Surgical

Case studies and small series have reported that some patients with RE respond in some

Approximately a hundred patients with West or Lennox-Gastaut syndromes have been treated with IVIg with widely varying results. The treatment has resulted in reduction in the number of seizures with improvement in the EEG in about half of the cases. The positive effects were noted few days to several weeks to months after treatment. Relapses have been

Successful use of IVIg as initial monotherapy in LKS has been reported in case studies and after initial therapy by steroids or antiepileptic drugs and steroids in only few patients. Case studies on the use of IVIg in RE have suggested that monthly IVIg therapy (0.4 g/kg for 5 days at 4-week interval followed by monthly maintenance IVIg) may ameliorate disease in patients who are refractory to antiepileptic drugs or steroids and PE (EFNS task force, 2008).



Narcolepsy with cataplexy (NC) is caused by substantial loss of hypocretin neurons. NC patients carry the HLA-DQB1\*0602 allele suggesting that hypocretin neuron loss is due to

There are some case studies that report that IVIg treatment initiated before 9 months disease duration has some clinical efficiency. The unaffected CSF hypocretin-1 levels and lack of autoantibodies suggest that any autoimmune process occurs very early in NC. The

Alzheimer's Disease (AD) is the most common neurodegenerative disorder leading to dementia. The pathological hallmarks of AD are extracellular accumulation of Ab peptides,

Clinical studies of active immunization in humans with AD were complicated by the development of meningoencephalitis in 6% of the patients treated with vaccine AN1792 in a phase II clinical trial. Furthermore, only 20% of the patients immunized with AN1792

However, progress was made with the discovery that peripheral administration of antibodies against Ab peptide could reduce amyloid burden to a similar extent as active immunization. Passive immunization had the advantage that the potentially harmful

Based on the finding that externally administered antibodies were able to protect mice from AD, it was hypothesized that high titres of natural anti-Ab antibodies may protect humans from AD, while low levels may predispose certain individuals to the development of AD. Studies have found reduced levels of anti-Ab antibodies both in the serum and CSF of

as senile plaques and intracellular neurofibrillary tangles composed of tau proteins.

are refractory to other therapies (good practice point).

**10. IVIg in therapy of narcolepsy with cataplexy (NC)** 

final IVIg effect needs to be investigated in RCTs (Knudsen et al, 2010).

**11. IVIg in therapy of Alzheimer's disease (AD)** 

developed a twofold increase in anti-Ab antibodies.

activation of host T cells could be avoided.

cycles may be repeated after 2–6 weeks.

treatment also may be considered.

common.

Recommendation:

an autoimmune attack.

measure to treatment with IVIG (class IV).

IVIg is used increasingly in neurological diseases.

Its efficacy has been proved in GBS, CIDP and MMN, where it is considered as the first-line treatment. However, questions remain regarding the dose, timing and duration of IVIg treatment in these disorders.

It is also successfully used in acute exacerbations of MG and as a short-term treatment of severe MG. It is recommended in SPS, in some paraneoplastic syndromes and as a secondline treatment in combination with prednisone in dermatomyositis and a treatment option in polymyositis.

In MS, IVIg is indicated mainly in reducing disease activity during pregnancy and breastfeeding.

In addition to these major indications, IVIg is increasingly used even in such conditions where the strong evidence is currently lacking, like refractory epilepsy, narcolepsy, post polio syndrome.

According to preliminary data, IVIg might be a promising candidate for the treatment of (AD). Large-scale randomized trials are under way, and the results of these studies are awaited eagerly worldwide.

When considering treatment options, it is important to notify that uncontrolled use may lead to high costs and limited availability of IVIg. Careful selection of patients who will benefit from IVIg is extremely important.

ABBREVIATIONS:

AChR: acetylcholine receptor

AD: Alzheimer's Disease

ADEM: Acute-disseminated encephalomyelitis

AIDP: acute inflammatory demyelinating polyneuropathy

AMAN: acute motor axonal neuropathy

AMSAN: acute motor and sensory axonal neuropathy

CIDP: chronic idiopathic demyelinating polyneuropathy

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CSF: cerebrospinal fluid DM: dermatomyositis DRIE: Drug-resistant infantile epilepsy GBS: Guillain – Barre syndrome IBM: inclusion body myositis IVIg: intravenous immunoglobulin LEMS: Lambert-Eaton myasthenic syndrome LRPN: Lumbosacral radiculoplexus neuropathy MGUS: monoclonal gammopathy of undetermined significance MMN: multifocal motor neuropathy MG: Myasthenia gravis MS: Multiple Sclerosis MuSK: muscle-specific tyrosin kinase NC: Narcolepsy with cataplexy NMO: Neuromyelitis optica OMS : opsoclonus–myoclonus syndrome PE: Plasma exchange PM: polymyositis PPS: Post-polio syndrome RCT: randomized controlled trials RRMS: Relapsing Remitting Multiple Sclerosis SPS: Stiff-person syndrome SSN: Paraneoplastic sensory neuronopathy

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CSF: cerebrospinal fluid DM: dermatomyositis

MG: Myasthenia gravis MS: Multiple Sclerosis

PE: Plasma exchange PM: polymyositis

**13. References** 

2377

PPS: Post-polio syndrome

SPS: Stiff-person syndrome

RCT: randomized controlled trials

DRIE: Drug-resistant infantile epilepsy GBS: Guillain – Barre syndrome IBM: inclusion body myositis IVIg: intravenous immunoglobulin

MMN: multifocal motor neuropathy

MuSK: muscle-specific tyrosin kinase NC: Narcolepsy with cataplexy NMO: Neuromyelitis optica

OMS : opsoclonus–myoclonus syndrome

RRMS: Relapsing Remitting Multiple Sclerosis

SSN: Paraneoplastic sensory neuronopathy

LEMS: Lambert-Eaton myasthenic syndrome LRPN: Lumbosacral radiculoplexus neuropathy

MGUS: monoclonal gammopathy of undetermined significance

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**18** 

**Cellular Based Therapies for** 

*2Thomas Jefferson University, Philadelphia,* 

*1University of Nottingham,* 

*1United Kingdom* 

*2USA* 

**the Treatment of Multiple Sclerosis** 

James Crooks1, Guang-Xian Zhang2 and Bruno Gran1

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) and the primary cause of non-traumatic neurologic disability in the western world. Infiltration of myelin-specific effector T cells into the CNS is thought to cause demyelination and loss of axons resulting in deficient signal conduction and clinical onset of the disease. Although previously thought to be initiated by T helper 1 (Th1) cells, it has become evident that Th17 cells are also involved (Cua 2003). In addition, CD8+ T cells, macrophages, and B cells are also found in inflammatory infiltrates in the CNS of affected individuals. During the initial phases of the disease, once the myelin-specific peripherally activated T cells penetrate the CNS, they are re-activated by antigen presenting cells presenting their target antigen within the CNS and act to cause damage to axonal myelin through the activation of macrophages and the release of myelin toxic substances (Aktas,

One of the main obstacles to recovery and to the treatment of MS is the relatively low efficiency of spontaneous remyelination of axons by oligodendrocytes. In the majority of cases during the early phases of the disease a large amount of oligodendrocytes and their precursors are preserved within the characteristic demyelination plaques and retain the ability to remyelinate. Despite this resident population of remyelinating cells it has been shown that over time remyelination becomes incomplete and fails, resulting in the

The direct cause of MS remains unknown but it seems most likely to be a mixture of both genetic susceptibility and environmental factors. Genetic factors had been long suspected to affect the chances of an individual developing MS. It has been known for some time that there is a familial link to the disease with a sharp increase in disease probability if a family member has the disease (Dyment, Ebers et al. 2004), with a direct correlation between how closely related the affected individual is and the probability of developing the disease. The importance of genetic factors was underscored by the fact that adopted children have no statistically significant increase in there disease susceptibility compared to the general population, even if any of their adoptive family members have the disease. Other genetic factors such as gender and race have also been shown to have an effect (Sospedra and

irreversible neurological damage associated with the disease (Franklin 2002).

**1. Introduction** 

Waiczies et al. 2007).

Martin 2005).

