8/22/2013

Intravenous Immune Globulin (IVIg) Therapy

For Neurologic Diseases

  1. Marinos C. Dalakas, MD
+Author Affiliations
  1. From the National Institutes of Health, Bethesda, Maryland. For the current author address, see end
     of text. For definitions of terms used in this article, see glossary at end of text. Acknowledgment: 
    The author thanks B.J. Hessie for skillful editing. Requests for Reprints: Marinos
     C. Dalakas, MD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, 
    Room 4N248, 10 Center Drive, MSC 1382, Bethesda, MD 20892-1382.

    Abstract

    High-dose intravenous immune globulin (IVIg) has emerged as an important therapy for various neurologic diseases.
     Different interpretations of clinical trial results; the expected benefit of IVIg compared with that of alternate therapies;
     and issues about IVIg's safety, cost, and mechanisms of action have raised concern and uncertainty among practitioners.
     To clarify these areas, this paper examines the clinical, serologic, and immunologic data on more than 110 patients with various autoimmune neurologic
     diseases who received IVIg during the past 6 years at the National Institute of Neurological Disorders and Stroke. It also reviews work by other investigators 
    on the efficacy, risks, benefits, and mechanisms of the action of IVIg in these diseases.
    In controlled clinical trials, IVIg has been effective in treating the Guillain-Barre syndrome, multifocal motor neuropathy,
     chronic inflammatory demyelinating polyneuropathy, and dermatomyositis. 
    In other controlled or open-label trials and case reports, IVIg produced improvement in several patients with the Lambert-Eaton myasthenic 
    syndrome and myasthenia gravis but had a variable, mild, or unsubstantiated benefit in some patients with inclusion-body myositis, paraproteinemic
     IgM demyelinating polyneuropathy, certain intractable childhood epilepsies, polymyositis, multiple sclerosis, optic neuritis,
     and the stiff-man syndrome. The primary adverse reaction was headache; aseptic meningitis, skin reactions, thromboembolic events, and 
    renal tubular necrosis occurred rarely. The most relevant immunomodulatory actions of IVIg, operating alone or in combination, are inhibition of 
    complement deposition, neutralization of cytokines, modulation of Fc-receptor-mediated phagocytosis, and down-regulation of autoantibody production. 
    Therapy with IVIg is effective for certain autoimmune neurologic diseases, but its spectrum of efficacy has not been fully established. Additional controlled clinical trials are needed.
    By the American College of Physicians

    Intravenous Immunoglobulin in Autoimmune Neuromuscular Diseases

    1. Marinos C. Dalakas, MD
    [+] Author Affiliations
    1. Author Affiliations: Neuromuscular Diseases Section, National Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, Md.

    ABSTRACT

    Context  Intravenous immunoglobulin (IVIG) enhances immune homeostasis by modulating expression and function of Fc 
    receptors, interfering with activation of complement and production of cytokines, providing anti-idiotypic antibodies, and 
    affecting the activation and effector functions of T and B cells. These mechanisms may explain the effectiveness
     of IVIG in autoimmune neuromuscular disorders.
    Objective  To systematically review the current status of the treatment of autoimmune neuromuscular 
    diseases with IVIG, with emphasis on controlled trials.
    Data Sources  Peer-reviewed publications identified through MEDLINE (1966-2003), EMBASE (1974-2003), and
     references from bibliographies of pertinent articles. Each autoimmune neuromuscular disease term was searched 
    in combination with the term intravenous immunoglobulin.
    Study Selection and Data Extraction  Criteria for selection of studies included controlled study design, English
     language, and clinical pertinence. Data quality was based on venue of publication and relevance to clinical care.
    Data Synthesis  Outcomes of controlled trials indicate that IVIG at a total dose of 2 g/kg is effective as first-line
     therapy in Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor 
    neuropathy and as second-line therapy in stiff-person syndrome, dermatomyositis, myasthenia gravis, and 
    Lambert-Eaton myasthenic syndrome. In other controlled studies, IVIG produced a modest, variable, and transient
     but not statistically significant benefit in patients with inclusion body myositis and paraproteinemic 
    anti–myelin-associated glycoprotein antibody demyelinating polyneuropathy. Intravenous immunoglobulin is
     not effective in patients with multiple sclerosis who have established weakness or optic neuritis. 
    In myasthenia gravis, it should be reserved for difficult cases or before thymectomy in lieu of plasma exchange.
    Conclusion  Intravenous immunoglobulin is effective in many autoimmune neurologic diseases, but its 
    spectrum of efficacy, especially as first-line therapy, and the appropriate dose for long-term maintenance 
    therapy are not fully established. Further controlled studies of IVIG, combined with a dose-finding 
    effect, pharmacoeconomics, and quality-of-life assessments, are warranted to improve the evidence base


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    Erradicación de La poliomielitis

    Polio Tricisilla Adaptada

    March Of Dimes Polio History

    Dr. Bruno

    video

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    A 41-year-old man developed an acute illness at the age of 9 months during which, following a viral illness with headache, he developed severe weakness and wasting of the limbs of the left side. After several months he began to recover, such that he was able to walk at the age of 2 years and later was able to run, although he was never very good at sports. He had stable function until the age of 18 when he began to notice greater than usual difficulty lifting heavy objects. By the age of 25 he was noticing progressive difficulty walking due to weakness of both legs, and he noticed that the right calf had become larger. The symptoms became more noticeable over the course of the next 10 years and ultimately both upper as well as both lower limbs had become noticeably weaker.

    On examination there was wasting of the muscles of upper and lower limbs on the left, and massively hypertrophied gastrocnemius, soleus and tensor fascia late on the right. The calf circumference on the right exceeded that on the left by 10 cm (figure1). The right shoulder girdle, triceps, thenar eminence and small muscles of the hand were wasted and there was winging of both scapulae. The right quadriceps was also wasted. The wasted muscles were also weak but the hypertrophied right ankle plantar flexors had normal power. The tendon reflexes were absent in the lower limbs and present in the upper limbs, although the right triceps was reduced. The remainder of the examination was normal.

    Figure 1

    The patient's legs, showing massive enlargement of the right calf and wasting on the left

    Questions

    1
    What is that nature of the acute illness in infancy?
    2
    What is the nature of the subsequent deterioration?
    3
    What investigations should be performed?
    4
    What is the differential diagnosis of the cause of the progressive calf hypertrophy?

    Answers

    QUESTION 1

    An acute paralytic illness which follows symptoms of a viral infection with or without signs of meningitis is typical of poliomyelitis. Usually caused by one of the three polio viruses, it may also occur following vaccination and following infections with other enteroviruses.1 Other disorders which would cause a similar syndrome but with upper motor neurone signs would include acute vascular lesions, meningoencephalitis and acute disseminated encephalomyelitis.

    QUESTION 2

    A progressive functional deterioration many years after paralytic poliomyelitis is well known, although its pathogenesis is not fully understood.2 It is a diagnosis of exclusion; a careful search for alternative causes, for example, orthopaedic deformities such as osteoarthritis or worsening scoliosis, superimposed neurological disorders such as entrapment neuropathies or coincidental muscle disease or neuropathy, and general medical causes such as respiratory complications and endocrinopathies.3

    QUESTION 3

    Investigations revealed normal blood count and erythrocyte sedimentation rate and normal biochemistry apart from a raised creatine kinase at 330 IU/l (normal range 60–120 IU/l), which is commonly seen in cases of ongoing denervation. Electromyography showed evidence of denervation in the right APB and FDI with polyphasic motor units and complex repetitive discharges, no spontaneous activity in the left calf and large polyphasic units in the right calf consistent with chronic partial denervation. Motor and sensory conduction velocities were normal. A lumbar myelogram was normal. Magnetic resonance imaging (MRI) scan of the calves is shown in figure2.

    Figure 2

    Axial T1 weighted MRI scan (TR 588 ms, TE 15 ms) of the calves, showing gross muscle atrophy and replacement by adipose tissue on the left, and hypertrophy of the muscles on the right, with only minor adipose tissue deposition

    QUESTION 4

    The differential diagnosis of the progressive calf hypertrophy is given in the box.

    Causes of calf muscle hypertrophy

    Chronic partial denervation

    • radiculopathy

    • peripheral neuropathy

    • hereditary motor and sensory neuropathy

    • spinal muscular atrophy

    • following paralytic poliomyelitis

      Neuromyotonia and myokymia

    • Isaac's syndrome

    • generalised myokymia

    • neurotonia

    • continuous muscle fibre activity due to: chronic inflammatory demyelinating polyradiculopathy, Guillain Barre syndrome, myasthenia gravis, thymoma, thyrotoxicosis, thyroiditis

      Muscular dystrophies

      Myositis

      Infiltration

    • tumours

    • amyloidosis

    • cysticercosis

      Link here