Guidelines on the Use of Intravenous Immune Globulin for Neurologic Conditions

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Canada's per capita use of intravenous immune globulin (IVIG) grew by approximately 115% between 1998 and 2006, making Canada one of the world's highest per capita users of IVIG. It is believed that most of this growth is attributable to off-label usage. To help ensure IVIG use is in keeping with an evidence-based approach to the practice of medicine, the National Advisory Committee on Blood and Blood Products (NAC) and Canadian Blood Services convened a panel of national experts to develop an evidence-based practice guideline on the use of IVIG for neurologic conditions. The mandate of the expert panel was to review evidence regarding use of IVIG for 22 neurologic conditions and formulate recommendations on IVIG use for each. A panel of 6 clinical experts, one expert in practice guideline development and 4 representatives from the NAC met to review the evidence and reach consensus on the recommendations for the use of IVIG. The primary sources used by the panel were 2 recent evidence-based reviews. Recommendations were based on interpretation of the available evidence and, where evidence was lacking, consensus of expert clinical opinion. A draft of the practice guideline was circulated to neurologists in Canada for feedback. The results of this process were reviewed by the expert panel, and modifications to the draft guideline were made where appropriate. This practice guideline will provide the NAC with a basis for making recommendations to provincial and territorial health ministries regarding IVIG use management. Recommendations for use of IVIG were made for 14 conditions, including acute disseminated encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, dermatomyositis, diabetic neuropathy, Guillain-Barré syndrome, Lambert-Eaton myasthenic syndrome, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, opsoclonus-myoclonus, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, polymyositis, Rasmussen's encephalitis, and stiff person syndrome; IVIG was not recommended for 8 conditions including adrenoleukodystrophy, amyotropic lateral sclerosis, autism, critical illness polyneuropathy, inclusion body, myositis, intractable childhood epilepsy, paraproteinemic neuropathy (IgM variant), and POEMS syndrome. Development and dissemination of evidence-based clinical practice guidelines may help to facilitate appropriate use of IVIG.

Section snippets

Description of Intravenous Immune Globulin

INTRAVENOUS IMMUNE GLOBULIN (IVIG) is a fractionated blood product consisting of concentrated immune globulin, primarily IgG, derived from human plasma in pools of 3000 to 10 000 or more donors. Intravenous immune globulin was first introduced in the early 1980s for the treatment of primary humoral immunodeficiencies and is currently licensed by Health Canada for treatment of primary and secondary immunodeficiency diseases, allogenic bone marrow transplantation, chronic B-cell lymphocytic

Expert Panel

Letters of invitation were sent to several neurologists across Canada, regarded by their peers as experts in their field. The panel consisted of 6 clinical experts, one expert in practice guideline development and 4 representatives from the NAC (Table 2).

The panel met in Toronto on September 9 and 10, 2004. Panel members were asked to declare any potential conflicts of interest. Conflicts were declared and noted by the Chair.

Clinical Conditions

The expert panel evaluated the use of IVIG for 22 neurologic

Clinical Description

Acute disseminated encephalomyelitis (ADEM) is an uncommon, usually self-limited, disease that predominantly occurs in children and young adults. ADEM often follows a viral infection or immunization. Patients typically present with fever, meningeal signs, myelopathy, and acute encephalopathy. The most common neurologic signs are motor deficits (eg, ataxia, hemiparesis) and impaired consciousness.

ADEM is thought to be an autoimmune disorder of the central nervous system (CNS) in which myelin

Clinical Description

Adrenoleukodystrophy (ALD) is an X-linked inherited disorder of peroxisomal metabolism that produces progressive CNS degeneration associated with CNS demyelination. The abnormality in peroxisomal metabolism results in accumulation of very-long-chain fatty acids (VLCFA), and the disease can be diagnosed by measurement of VLCFA in serum. Some patients require DNA analysis for diagnosis. Adrenoleukodystrophy affects both the cerebral and spinal cord white matter (adrenomyeloneuropathy), with much

Clinical Description

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the upper and lower motor neurons leading to progressive weakness, disability, and death. Sporadic ALS has an annual incidence of 1 to 2 per 100 000 population and peaks between ages 55 and 75 years. In 5% to 10% of cases, the disorder is autosomal dominant. Familial ALS starts about 10 years earlier than the sporadic form of the disorder.

Sixty percent of patients present with painless, progressive, focal, and asymmetric

Clinical Description

Autism is a neurodevelopmental disorder characterized by severe deficits in social and communicative skills, abnormal behaviors, and often global developmental delay. The term autism spectrum disorder is more commonly used, as the clinical features and severity of impairment in social and communicative skills can be highly variable. The incidence of autism spectrum disorder is approximately 5 per 10 000 children.

Most children are diagnosed between ages 1 and 3 years, when their deficits in

Clinical Description

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired demyelinating peripheral neuropathy of presumed autoimmune etiology, which presents either as a chronically progressive or relapsing/remitting disorder. Patients experience progressive weakness in all 4 limbs accompanied by numbness, impaired proprioception, and ataxia. Cranial nerves may be involved. Symptoms develop insidiously over weeks to months (arbitrarily defined minimum progression of 8 weeks) and may lead to loss

Clinical Description

Critical illness polyneuropathy (CIP) can develop in patients with multiorgan failure and sepsis. This is an axonal sensorimotor neuropathy associated with flaccid paralysis and respiratory weakness. Patients are often identified as it becomes apparent that they are having difficulty weaning from the ventilator. The precise etiology of CIP is not known; however, medications such as neuromuscular blocking agents and steroids may play a role. An underlying inflammatory process may be involved,

Clinical Description

Dermatomyositis can occur in both adults and children. In children, dermatomyositis is the most common inflammatory myopathy. Rash is associated with muscle weakness, and some patients will have the rash with very little evidence of muscle involvement. The rash is heliotrope in color and commonly presents on the face, extensor surfaces of extremities, and sun-exposed areas. The weakness can range from very mild to very severe.

Serum creatine kinase (CK) is frequently elevated in dermatomyositis

Diabetic Neuropathy

Diabetic neuropathy affects 50% to 60% of patients with type 1 diabetes mellitus of more than 10 years in duration and, likely, a similar number of type 2 diabetes mellitus patients. Most patients are either asymptomatic or mildly symptomatic. There are many subtypes of diabetic neuropathy with the most common being distal symmetrical diabetic polyneuropathy. Mononeuropathies (other than carpal tunnel syndrome) and asymmetric regional neuropathies are less common.

Proximal asymmetric lower limb

Clinical Description

Guillain-Barré syndrome (GBS) is the most common cause of acute flaccid paralysis, with an annual incidence of 2 per 100 000. This condition is characterized by rapidly evolving symmetrical limb weakness, facial and bulbar paralysis, loss of tendon reflexes, and absence of or mild sensory signs. Nearly 50% of patients become bedridden within a few days, and 25% of cases develop respiratory failure that requires intensive care unit admission for assistive mechanical ventilation and for monitoring

Clinical Description

Inclusion body myositis (IBM) is very different from dermatomyositis and polymyositis. Inclusion body myositis is usually a disease of older adults and is likely the most common newly acquired inflammatory myopathy in patients older than 65 years. Inclusion body myositis can be seen in younger patients but is rarely seen in those younger than 50 years. There is a very rare inherited disorder that has similar pathology to acquired IBM. Patients present with painless slowly progressive muscle

Recommendation

Based on consensus by the expert panel, pathologic confirmation by means of a skeletal muscle biopsy is required for the diagnosis of IBM. It is critical that the muscle specimen be procured, processed, and interpreted in a laboratory familiar with the correct handling of muscle biopsy specimens (including electron microscopy) and that the final interpretation be made by an expert in neuromuscular pathology.

Intravenous immune globulin is not recommended for the treatment of IBM.

Clinical Description

Epilepsies are characterized by recurrent, spontaneous and transient paroxysms of electrical discharges in the brain. Epileptic syndromes are defined based on seizure type, electroencephalogram (EEG) features, age of onset, and clinical course. At least 10% to 20% of childhood epilepsies are intractable, defined as failure to control seizures after an adequate trial of first-line antiepileptic medications. Although epilepsy is not generally considered an immunologic disorder, rare epileptic

Recommendation

Intravenous immune globulin is not recommended for the treatment of intractable childhood epilepsy.

Clinical Description

The Lambert-Eaton myasthenic syndrome (LEMS) is a rare acquired autoimmune disorder with autoantibodies directed against voltage-gated calcium channels (VGCC) on the presynaptic nerve terminal of the neuromuscular junction and of autonomic synapses. Patients have weakness and autonomic symptoms. The differential diagnosis includes myasthenia gravis, other disorders of neuromuscular transmission, myopathies, and peripheral neuropathies.

The diagnosis of LEMS can be made with single-fiber

Clinical Description

Multifocal motor neuropathy (MMN) presents as slowly progressive muscle weakness and wasting within the territory of individual motor nerves and with a predilection for the distal upper limbs. Focal cramps and fasciculations are common, particularly after exercise. Sensory symptoms and signs are notably absent on both clinical and electrophysiologic examination. The electrodiagnostic hallmark of MMN is finding focal conduction blocks in motor nerves outside regions normally prone to nerve

Clinical Description

Multiple sclerosis (MS) is the most common neurologic disability in young adults with a prevalence of one in 500 to 1000 in Canada. Most patients first present with clinical symptoms between 20 and 40 years of age, although the disease may have its onset in childhood or late adulthood. Most patients (approximately 85%) initially have a relapsing-remitting course that typically evolves into a secondary progressive course over 20 or more years. About 10% of patients experience a predominantly

Clinical Description

Myasthenia gravis is an acquired autoimmune disease characterized by the formation of autoantibodies to the acetylcholine receptor (AChR) and fatigable weakness. The incidence of myasthenia gravis is 7 per 1 000 000, and the prevalence is 75 to 125 per million. Women are affected 1.4 times more frequently than men, particularly those younger than 40 years. The differential diagnosis includes psychogenic weakness, chronic fatigue, myopathies, and cranial nerve compression syndromes.

Patients with

Clinical Description

Opsoclonus-myoclonus syndrome is a rare neurologic disorder characterized by an unsteady, trembling gait, myoclonus (brief, shock-like muscle spasms), and opsoclonus (irregular, rapid eye movements). Other symptoms may include difficulty speaking, poorly articulated speech, or an inability to speak. A decrease in muscle tone, lethargy, irritability and malaise may also be present. The underlying basis of this disorder is thought to be immune-mediated. Opsoclonus-myoclonus typically presents

Clinical Description

Most patients with IgM paraproteinemic demyelinating neuropathy present with a chronic, slowly progressive, distal, and predominantly sensory neuropathy. Patients usually experience prominent gait ataxia, paraesthesias, and numbness in the hands with impaired dexterity and coarse tremors. Although vibration sense and position sense are severely impaired, there is no or relatively little distal weakness. The disease progresses very slowly over months to years. Men are more commonly affected than

Clinical Description

Simple motor tics are common, affecting up to 1% to 2% of school-age children. The association of rapid-onset tics associated with obsessive-compulsive disorder (OCD) in the context of recovery from streptococcal infection (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections [PANDAS]) was first reported in 1994. Molecular mimicry between streptococcal antigens and the CNS have been hypothesized to underlie Sydenham's chorea, a well-recognized

Clinical Description

A chronic progressive and predominantly motor neuropathy resembling CIDP is the major clinical manifestation of POEMS syndrome. Peak incidence is in the fifth and sixth decades of life, and it predominantly occurs in men. Many patients are initially thought to suffer from idiopathic CIDP until an IgG or IgA paraprotein is detected by a careful search with protein electrophoresis or immunofixation electrophoresis. Most patients have a λ light chain containing M protein peak that is usually

Clinical Description

Polymyositis usually presents in adults, with slowly progressive proximal muscle weakness, particularly affecting the hip and shoulder girdles. Some patients will have associated muscle pain. The disorder can occur as an isolated autoimmune muscle disease or as part of a specific connective tissue disease, such as systemic lupus erythematosus or mixed connective tissue disease. Serum CK is usually elevated and is often extremely high. Electromyography abnormalities are present in most patients

Clinical Description

Rasmussen's encephalitis is a rare progressive form of epilepsy with onset in the first decade of life. The disorder is associated with severe focal epilepsy, lateralized brain atrophy, and progressive CNS impairment. Outcome is uniformly poor. Surgical resection of the affected hemisphere is viewed as the mainstay of therapy but has significant morbidity. Evidence that Rasmussen's encephalitis has an autoimmune basis stems from pathologic evidence of inflammation in resected brain tissue.

Clinical Description

Stiff person syndrome is an uncommon acquired disorder that produces severe disabling muscle spasms and rigidity. Approximately 50% of patients have antiglutamic acid decarboxylase (GAD65) antibodies. Stiff person syndrome is thought to have an autoimmune etiology and is associated with other autoimmune disorders, most frequently diabetes. The disorder can affect children or adults. Axial muscles and limbs are usually affected; however, there is a variant with restricted limb involvement. Drugs

Process

Feedback on this practice guideline was obtained from neurologists in Canada. The process was informed by the Practitioner Feedback methodology used to create clinical practice guidelines on cancer care in Ontario.4 A draft of this practice guideline, along with an accompanying letter of explanation and feedback survey, was e-mailed to members of the Canadian Neurological Society. Practitioners were given the option of faxing their completed survey or providing their responses online through a

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