THE USE OF INTRAVENOUS IMMUNOGLOBULIN IN

TREATMENT OF NEUROLOGICAL DISEASES.

DEPARTMENT OF NEUROLOGY

The efficacy of IVIg with specific autoimmune-mediated neuromuscular diseases has been established in controlled clinical trials.

IVIg is often prescribed where plasma exchange (PE) may have similar efficacy. However, PE is not universally available and requires specially trained personnel and may have greater side effects in certain situations

Classification of evidence levels Ia Evidence (E) obtained from MA of randomised

controlled trials( RCT), SR of RCTs Ib at least one RCT IIa at least one well-designed controlled study

without randomisation or cohort studies IIb at least one other type of well-designed quasi-

experimental study or case cotrol or cohort studies with a high risk

III well-designed non-experimental descriptive studies

IV expert opinions

Classification of grades of recommendations A. Evidence levels Ia, Ib : established as effective,

ineffective, or harmful B. Evidence levels IIa : probably effective,

ineffective, or harmful C. Evidence levels IIb, III : possibly effective,

ineffective, or harmful D. Evidence levels III, IV : Practice Points

Guillain-Barré syndrome

This is disorder causing demyelination and axonal degeneration, resulting in acute, ascending and progressive neuropathy. It is characterised by weakness, paraesthesiae, and hyporeflexia. In severe cases, muscle weakness may lead to respiratory failure. Severe autonomic dysfunction may also occur.

Guillain-Barré syndrome

Intravenous immunoglobulin (IVIG) 0.4 g/kg/day for 5 days or plasma exchange (PE) can be used as first-line treatment and are considered to be equally effective (grade A recommendation, level Ia evidence /SR of RCTs –Cochrane 2006)

IVIG for children with GBS should be reserved for those with ( AAN-2003)

Rapidly progressing weakness Worsening respiratory status or need for

mechanical ventilation Significant bulbar weakness Inability to walk unaided

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) CIDP is an chronically progressive, acquired

immune-mediated inflammatory disorder of the peripheral nervous system but often can have central nervous system involvement.

In many ways, CIDP can be considered the chronic equivalent of acute inflammatory demyelinating polyradiculoneuropathy (AIDP), the most common form of Guillain-Barré syndrome (GBS).

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)

Patients with very mild symptoms which do not or only slightly interfere with activities of daily living may be monitored without treatment ( good practice point ). Treatment should be considered for patients with moderate or severe disability. IVIG (2 g/kg in 2 to 5 days) ( grade A recommendation, level Ia evidence/SR of RCTs2002 - Cochrane). A Cochrane SR found no significant difference in efficacy

between IVIg and plasma exchange or IVIg and corticosteroids

Multifocal Motor Neuropathy (MMN)

Multifocal motor neuropathy (MMN) with conduction block is an acquired immune-mediated demyelinating neuropathy with slowly progressive weakness, fasciculations, and cramping, without significant sensory involvement.

Duration of disease prior to diagnosis ranges from several months to more than 15 years.

Multifocal Motor Neuropathy (MMN) As there is no other treatment of proven benefit,

the recommendation is to use IVIG (2 g/kg in 2 to 5 days) as a first-line treatment (grade A

recommendation, level Ib evidence/ RCTs 1995-2001-Neurology and Brain).

If the initial IVIG treatment is effective, repeated infusions should be considered ( grade C ,level III evidence – study of van den Berg et al- Brain 2002).

Acute-disseminated encephalomyelitis (ADEM) ADEM is an immune mediated disease of the

brain. It usually occurs following a viral infection but

may appear following vaccination, bacterial or parasitic infection, or even appear spontaneously.

It involves autoimmune demyelination.

Acute-disseminated encephalomyelitis (ADEM) IVIG may have a favourable effect in the

treatment of ADEM, and, therefore, it should be tried (0.4 g/kg/day for 4 to 5 consecutive days) in patients with lack of response to high-dose steroids (grade C, level III evidence / study of Kleiman- Neurol 1995 et Sahlas –Neurology 2000.).

The cycles may repeated.

Multiple Sclerosis

Multiple sclerosis (MS) is an idiopathic inflammatory demyelinating disease of the CNS. Patients with MS commonly present with an individual mix of neuropsychological dysfunction, which tends to progress over years to decades.

IVIG in Multiple Sclerosis The negative results of the Prevention of Relapses

with IVIG (PRIVIG) Study challenge recommendations for IVIG as a second-line treatment for relapsing-remitting multiple sclerosis (RRMS). ( level B/ EFNS guideline 2008)

IVIG cannot be recommended for treatment in secondary progressive MS ( level A ), and cannot be recommended as treatment for chronic symptoms in MS ( level A /EFNS 2008).

Dermatomyositis (DM) DM is an idiopathic inflammatory myopathy

(IIM) with characteristic cutaneous findings. Progressive proximal symmetrical weakness,

elevated levels of muscle enzymes, an abnormal finding on electromyography, and an abnormal finding on muscle biopsy, and with cutaneous disease.

Dermatomyositis (DM) IVIG is recommended as a second-line treatment

in combination with prednisone for patients with DM who have not adequately responded to corticosteroids or in aggressive disease requiring hospitalisation with involvement of the respiratory and bulbar musculature (grade B recommendation, level IIa evidence/ Controlled and open-label studies of Sansome -Arch Dis Child 1995 and Cherin –J rheumatol)

Polymyositis

the idiopathic inflammatory myopathies. symmetric proximal muscular weakness, elevated

serum muscle enzyme levels, electromyographic evidence of myopathic abnormalities, and characteristic findings at muscle biopsy.

Polymyositis

IVIG may be considered amongst the treatment options for patients with polymyositis not responding to first-line immunosuppressive treatment ( level C- guideline of EFNS 2008 ).

Myasthenia Gravis (MG)

MG is a relatively rare autoimmune disorder of peripheral nerves in which antibodies form against acetylcholine (ACh) nicotinic postsynaptic receptors at the myoneural junction.

↓ ACh receptors results in a characteristic pattern of progressively reduced muscle strength with repeated use of the muscle and recovery of muscle strength following a period of rest.

Myasthenia Gravis (MG) IVIG is an effective treatment for acute exacerbations

of MG and for short-term treatment of severe MG (grade A recommendation, level Ib evidence/ RCT of Zinman L et al – Neurology 2007). IVIG is similar to PE regarding effect. This treatment is safe also for children, during pregnancy, and for elderly patients with complicating disorders.

There is not sufficient evidence to recommend IVIG for chronic maintenance therapy in MG alone or in combination with other immunoactive drugs.(grade A, level Ia evidence / SR of RCTs – Cochrane 2003)

Paraneoplastic Syndromes paraneoplastic Lambert-Eaton myasthenic syndrome (LEMS) LEMS is a rare disorder of neuromuscular

transmission. It is a presynaptic disorder of neuromuscular transmission in which quantal release of acetylcholine (ACh) is impaired → include proximal muscle weakness, depressed tendon reflexes, posttetanic potentiation, and autonomic changes.

between 50% and 70% of patients with LEMS have an identifiable cancer, majority with SCLC.

Paraneoplastic Syndromes paraneoplastic Lambert-Eaton myasthenic

syndrome (LEMS)

Intravenous immunoglobulin therapy may be tried in LEMS especially in paediatric neuroblastoma patients if other treatments have failed or are inappropriate (grade A recommendation, level Ia evidence/ SR of RCTs – Cochrane 2005).

Drug-Resistant Epilepsy Rasmussen's encephalitis (RE) RE, also Chronic Focal Encephalitis (CFE), is a rare,

progressive neurological disorder by : frequent and severe seizures, loss of motor skills and speech, hemiparesis,encephalitis ,dementia, and mental deterioration. The disorder, which affects a single cerebral hemisphere, generally occurs in children under the age of 15.

→ Drug resistant/drug refractory seizures, Lennox-Gastaut syndrome

Drug-Resistant Epilepsy Rasmussen's encephalitis (RE) IVIG seems to have a favourable effect in

Rasmussen's encephalitis (RE) and may be tried in selected patients that are refractory to other therapies (grade C recommendation, level IIb evidence/ Studies of Vallani – neurology 2001and of Granata- Neurol 2003 ). IVIG has been administered at doses of 0.4 g/kg/day for 4 to 5 consecutive days, the cycles may be repeated after 2 to 6 weeks.

Intractable childhood epilepsy

in intractable childhood epilepsy (Lennox-

Gastaut syndrome, West syndrome, early myoclonic encephalopathy, Landau-Kleffner syndrome, IVIG can be used if other antiepileptic therapies have failed ( grade D, level III evidence/ series or case reports – Neurol and Eur J Pediatr)

REFERENCES EFNS guideline 2008

102. van Doorn PA, Brand A, Strengers PF etal. High-dose intravenous immunoglobulintreatment in chronic inflammatorydemyelinating polyneuropathy: a doubleblind,placebo-controlled, crossover study.Neurology 1990;40:209–12.103. Dyck PJ, Litchy WJ, Kratz KM et al. A plasmaexchange versus immune globulin infusiontrial in chronic inflammatory demyelinatingpolyradiculoneuropathy. Ann Neurol1994;36:838–45.104. Hahn AF, Bolton CF, Zochodne D, FeasbyTE. Intravenous immunoglobulin treatmentin chronic inflammatory demyelinatingpolyneuropathy. A double-blind, placebocontrolled,cross-over study. Brain1996;119(suppl):1067–77.105. Mendell JR, Barohn RJ, Freimer ML etal. Randomized controlled trial of IVIg inuntreated chronic inflammatory demyelinatingpolyradiculoneuropathy. Neurology2001;56:445–9.

107. van Schaik IN, Winer JB, De Haan R, Vermeulen M. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2002;(2):CD001797. 108. Hughes RA, Donofrio P, Bril V et al; ICE Study Group. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol 2008;7:136–44. 109. Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst 2007;10:220–8. 110. Dalakas MC. Update on the use of intravenous immune globulin in the treatment of patients with inflammatory muscle disease. J Clin Immunol 1995;15:70S–5.

113. Choy EHS, Hoogendijk JE, Lecky B, Winer JB. Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis. Cochrane Database Syst Rev 2005;(3):CD003643. 114. Hughes RA, Raphael JC, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain- Barré syndrome. Cochrane Database Syst Rev 2006;(1):CD002063. 115. Maddison P, Newsom-Davis J. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev 2005:(2): CD003279. 116. Bain PG, Motomura M, Newsom-Davis J et al. Effects of intravenous immunoglobulin on muscle weakness and calciumchannel autoantibodies in the Lambert- Eaton myasthenic syndrome. Neurology 1996;47:678–83. 117. Muchnik S, Losavio AS, Vidal A et al. Longterm followup of Lambert-Eaton syndrome treated with intravenous immunoglobulin. Muscle Nerve 1997;20:674–8. 118. Peterlin BL, Flood W, Kothari MJ. Use of intravenous immunoglobulin in Lambert- Eaton myasthenic syndrome. J Am Osteopath Assoc 2002;102:682–4.

121. Azulay JP, Blin O, Pouget J et al. Intravenousimmunoglobulin treatment in patientswith motor neuron syndromes associatedwith anti-GM1 antibodies: a double-blind,placebo-controlled study. Neurology1994;44:429–32.122. van den Berg LH, Kerkhoff H, Oey PLet al. Treatment of multifocal motorneuropathy with high dose intravenousimmunoglobulins: a double blind, placebocontrolled study. J Neurol NeurosurgPsychiatry 1995;59:248–52.123. Federico P, Zochodne DW, Hahn AF et al.Multifocal motor neuropathy improved byIVIg: randomized, double-blind,placebo-controlled study. Neurology2000;55:1256–62.124. Leger JM, Chassande B, Musset L et al.Intravenous immunoglobulin therapy inmultifocal motor neuropathy: a doubleblind,placebo-controlled study. Brain2001;124:145–53.125. van den Berg-Vos RM, Franssen H,Wokke JH, van den Berg LH. Multifocalmotor neuropathy: long-term clinicaland electrophysiological assessment ofintravenous immunoglobulin maintenancetreatment. Brain 2002;125:1875–86.