Journal of Neuro-Ophthalmology, December 1991, Volume 11, Issue 4

Dysgammaglobulinemia in steroid-dependent optic neuritis: response to gammaglobulin treatment.

At the age of 12, a prematurely born boy with an otherwise unremarkable past medical history developed bilateral optic neuritis associated with transverse myelopathy. Over the ensuing 3 years, recurrent bouts of optic neuritis OU, with dyschromatopsia, and acuity and field loss (arcuate, central, and paracentral scotomas) were controlled with increasing doses of corticosteroids. However, the patient became steroid-dependent and experienced recurrent optic neuritis during multiple attempts at tapering the steroids. He developed optic atrophy and steroid complications, including cushingnoid features and growth maturation delay. Immunoglobulin G subclass 2 and 3 deficiencies were the only serologically detectable abnormalities. Administration of intravenous gammaglobulin (25 g monthly) allowed discontinuation of steroids without further ophthalmic or neurologic disease. Following steroid withdrawal and institution of gammaglobulin, the patient grew 6 inches within 2 years, regaining his vision, retrieving his stature, and normalizing his psychosocial development.

Journal of Clinical Neuro- ophlhalmology 11( 4): 241- 245, 1991. © 1991 Raven Press, Ltd., New York Dysgammaglobulinemia in Steroid- Dependent Optic Neuritis: Response to Gammaglobulin Treatment L. P. Frohman, M. D., S. D. Cook, M. D., and L. Bielory, M. D. At the age of 12, a prematurely born boy with an other­wise unremarkable past medical history developed bi­lateral optic neuritis associated with transverse myelop­athy. Over the ensuing 3 years, recurrent bouts of optic neuritis au, with dyschromatopsia, and acuity and field loss ( arcuate, central, and paracentral scotomas) were controlled with increasing doses of corticosteroids. However, the patient became steroid- dependent and ex­perienced recurrent optic neuritis during multiple at­tempts at tapering the steroids. He developed optic at­rophy and steroid complications, including cushingnoid features and growth maturation delay. Immunoglobulin G subclass 2 and 3 deficiencies were the only serologi­cally detectable abnormalities. Administration of intra­venous gammaglobulin ( 25 g monthly) allowed discon­tinuation of steroids without further ophthalmic or neu­rologic disease. Following steroid withdrawal and institution of gammaglobulin, the patient grew 6 inches within 2 years, regaining his vision, retrieving his stat­ure, and normalizing his psychosocial development. Key Words: Optic neuritis- Steroids- Dysgammaglob­ulinemia. From the Departments of Ophthalmology ( L. P. F.), Neurosci­ences ( L. P. F., S. D. C.), and Medicine ( L. B.), Univer~ ity of Med­icine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, U. S. A. Address correspondence and reprint requests to Dr. Leonard Bielory at Division of Allergy and Immunology, Immuno­ophthalmology, Research Laboratory, New Jersey Medical School, 185 South Orange Avenue, MSB E- 583, Newark, NJ 07103- 2714, U. S. A. 241 Although its etiology is obscure, the association of optic neuritis with demyelinating disease ( mul­tiple sclerosis) is irrefutable, but other conditions associated with it include autoimmune disorders ( 1), infections such as herpes zoster, and parain­fectious conditions such as Guillain- Barre syn­drome ( 2). Bilateral optic neuritis may occur days or weeks prior to or following an attack of trans­verse myelitis. This combination is called neuro­myelitis optica, or Devic's disease, and is consid­ered a variant of multiple sclerosis in children and young adults ( 3). Therapeutic intervention for optic neuritis is controversial. Severe visual loss is often treated with prednisone, but optic neuritis usually re­solves without specific treatment. The case of our patient is atypical in that all attempts at discontin­uation of steroid treatment resulted in recurrence of visual symptoms. Steroid- dependent optic neu­ropathy requiring corticosteroid maintenance ther­apy to prevent loss of vision is observed in patients with autoimmune optic neuropathies or with pri­mary autoimmune diseases, notably systemic lu­pus erythematosus ( 4). Distinguishing between id­iopathic optic neuritis and autoimmune optic neu­ropathy is essential for appropriate therapy, since the latter may require large doses ( 500- 3,000 mg/ day) of " pulse" methylprednisolone and/ or cyto­toxic drug treatment to preserve vision ( 4,5). These latter patients may harbor auto- antibodies capable of binding to optic nerve, such as the anticardio­lipin antibody ( 6,7). Although spontaneous reso­lution is the norm in typical optic neuritis, it is controversial whether steroids hasten recovery, a point under study by the present National Insti­tutes of Health ( NIH) Optic Neuritis Treatment Trial ( 8,9). 242 I. P. FROHMAN ET AI. CLINICAL REPORT A 15- year- old boy with a 3- year history of recur­rent steroid- dependent optic neuritis, delayed pu­berty, delayed maturation, and short stature was referred to the Immuno- Ophthalmology Service of University of Medicine and Dentistry of New Jer­sey, New Jersey Medical School in August of 1987. The patient was born in September, 1971, after 30 weeks' gestation, and was hospitalized for 5 weeks because of hyaline membrane disease. He attained normal growth and development throughout childhood and was in good health until April 1984, when he developed a viral syndrome consisting of nausea, vomiting, anorexia, abdominal pain, and diarrhea, which resolved spontaneously. This was followed by bilateral ocular pain and visual loss and intermittent attacks of headache. Computed tomographic ( CT) scan of the head was normal. The headaches improved after lumbar punctures on two separate occasions: the first lumbar punc­ture on May 12, with opening pressure of 280 mm H20 and concentrations of 170 x 103/ L white blood cells ( WBC), 5 x 103/ L red blood cells ( RBC), 2.8 mmol/ L glucose, ( serum glucose: 6.16 mmol/ L, and 0.58 giL protein; and the second lumbar puncture on May 14, with opening pressure of 160 mm H 2 0, 207 x 103/ L WBC, 3.1 mmol/ L glucose, ( serum glu­cose: 6.6 mmol/ L), and 1.14 giL protein. Tests for oligoclonal bands were negative. When urinary hesitancy and retention developed, the patient was reevaluated at another institution and found to have nuchal rigidity, equivocal plantar reflexes, sensory loss below the midchest, decreased strength in the lower extremities, and urinary and fecal incontinence. The vision was Counting fin­gers au with bilaterally sluggish pupillary re­sponses. Bilateral blurring of the optic disc mar­gins were noted. The erythrocyte sedimentation rate ( ESR) was 67mrnlhr, the antinuclear antibody negative. Repeat lumbar puncture revealed an opening pressure of 180 mm, an elevated protein ( 1.07 mg%) and pleocytosis ( 135 x 103 WBClL with 87% lymphocytes). Devic's syndrome ( optic neuritis with associated transverse myelopathy), possibly secondary to a diffuse parainfectious encephalomyelopathy, was diagnosed. Within 24 hours of methylpredniso­lone ( 96 mg p. o., q. i. d.), he experienced clinical improvement; the dose was decreased to 48 mg p. o., q. i. d. and replaced after 6 days by pred­nisone ( 40 mg ti. d.). The patient showed marked improvement of all neurologic symptoms within one week, with visual acuity of 20/ 25 00 and 20/ 30 J Clin Neuro- ophthalmol. Vol. 11, ,," as. A lumbar puncture revealed a pleocytosis ( 100 x 103 WBClL with 97% lymphocytes) and a normal glucose and protein with oligoclonal bands present. The ESR declined to 30 mrnlh. Elevated blood pressure prompted rapid tapering of the ste­roids; but with recurrence of optic neuritis ( 4 bouts within one year), the patient became steroid­dependent. Magnetic resonance imaging ( MRI) of the head in June 1985 was normal. A repeat lumbar puncture in July 1985 was acellular with normal total proteins, gammaglobulins, myelin basic pro­tein, and oligoclonal bands. In August 1985, after his fourth relapse, he underwent his first neuro­ophthalmic exam ( at another institution). His vi­sual acuity was 20170 00 and 20/ 60 as. American Optical color plates were 6115 correct 00 and 4/ 15 correct as. The pupils were recorded as 4- 5 mm au, sluggishly reactive to light, without relative afferent pupillary defect ( RAPD). Goldmann visual fields showed a superior arcuate field defect, as well as a paracentral scotoma 00, and a cecocen­tral scotoma as. Funduscopic examination re­vealed bilateral optic atrophy and pigmentary changes in the macula as. One month later, the CT and MRI scans of the head were normal, and the cerebrospinal fluid was normal with no oligo­clonal banding. Visual acuity had improved to 201 30 00 and 20/ 25 as, and the superior arcuate scotoma 00 and the cecocentral scotoma as had resolved. Over this 16- month period the patient's height had dropped from the 25th to the 5th percentile curve while his bone age was 13, with a chrono­logical age of 14 years. He was prepubertal and cushingnoid in appearance. The failure to grow and pubertal delay caused extensive psychosocial problems. Growth hormone was administered without effect. Alternative treatments ( e. g. cyclo­phosphamide, chlorambucil) for optic neuritis were considered and rejected because of associ­ated adverse effects, including carcinogenic poten­tial, sterility, and renal dysfunction. At this time multiple sclerosis was postulated, and he was re­ferred to the Multiple Sclerosis Center at the New Jersey Medical School. Pertinent findings, when seen, included a visual acuity of 20/ 20 au, a left Babinski sign, moon facies, " buffalo hump," and facial plethora. Over the next 15 months the pa­tient was maintained on steroid therapy with con­tinued retardation of growth, remaining below the 5th percentile for height, with his bone age 13 ( at the age of 16); his development was still prepuber­tal. He was referred to the Immuno- ophthalmology DYSGAMMAGLOBULINEMIA 243 Service of the New Jersey Medical School in Au­gust 1987 while on prednisone ( 35 mg every other day). The neuro- ophthalmic examination revealed best corrected Snellen acuity of 20/ 20 00 and 20/ 25 as. Ishihara color plates were 3 1/ 2 of 10 correct in the right eye and 2 of 10 correct in the left eye. The pupils were 5 mm OU, round, reactive to light bilaterally, sluggish in the left eye, with a + 2 left RAPD. Cranial nerve and slit lamp examinations were normal, with the exception of a scleral plaque at 11 o'clock as. Funduscopic examination was significant for bilateral disc pallor ( as> 00). The arterioles of both eyes were minimally narrowed with an increase in macular lutein pigment au. Subsequent examinations ( 11/ 87 and 4/ 88) were unchanged except for mild bilateral improvement on the Ishihara plates. The diagnostic laboratory tests and immunologic evaluations, including a lumbar puncture and skin punch biopsies, did not uncover an infectious or autoimmune etiology ( i. e., vasculitis). The blood count was normal. Tests for serum rheumatoid fac­tor, antinuclear, anti- smooth muscle, tularemia, leptospira, and rickettsia antibodies were negative. Assays for circulating antibodies directed against the retina and optic nerve ( performed at the Uni­versity of California, Davis) were negative ( 10). Angiotensin converting enzyme and lysozyme lev­els were normal, as were immunoglobulins A and M. The total IgG of 10 gIL was within the normal range ( 7.26- 10.85 gIL) for the patient's age group ( 11). Dysgammaglobulinemia was present, as evi­denced by decreased levels of IgG subclasses 2 and 3 ( IgG2: 0.85 gIL, reference range 1.17- 7.47; IgG3: 0.25 gIL, reference range 0.41- 1.29). Starting in December 1987, steroids were ta­pered and a monthly regimen of 500 mglkg ( 25 g) intravenous gammaglobulin [ IVIgG ( Sandoglobu­lin)] every 4 weeks was implemented, without any complications or recurrence of symptoms. The pa­tient received his last dose of steroids on June 21, 1988, while continuing IVIgG. At his last neuro- ophthalmic examination, in August 1989, his Snellen acuity was 20/ 20 + au, Ishihara color plates 3.5/ 10 correct 00 and 5/ 10 as, with a trace left RAPO measuring less than 0.3 log units, a normal tangent visual field with a 1/ 1,000 white test object OU. There was a trace of central desaturation to red with a 5/ 1,000 red object AD, and a hint of a cecocentral scotoma to 5/ 1,000 red as. The funduscopic examination was un­changed from the initial exam. In February 1990, MgG was decreased to 6- week intervals, and at his last visit with the Immunology Service ( 1/ 91), he had been off of steroids for 30 months, re­mained free of any new visual loss or other neu­rologic illness, and had grown an additional 6 inches. COMMENTS Immunoglobulins are the major effector mole­cules of the humoral immune system and are com­posed of proteins produced by cells of the B lym­phocyte lineage. Individuals lacking portions of the humoral immune system develop chronic in­fections ( e. g., meningitis, sinusitis, bronchitis, pneumonia, gastroenteritis) or autoimmune disor­ders ( e. g., systemic lupus erythematosus) ( 12). Re­placement therapy for humoral immunodeficien­cies originally consisted of using whole plasma, until immunoglobulin preparations from pooled human blood were isolated in 1952. Although orig­inally used for immune deficiency states, IVIgG was the topic of a recent NIH Consensus Develop­ment Conference which concluded that MgG was useful in a variety of other conditions in addition to primary immunodeficiencies, including idio­pathic thrombocytopenic purpura ( ITP), Kawasaki syndrome, cytomegalovirus pneumonia, and chronic lymphocytic leukemia ( 13). Since 1981, when IVIgG was first reported to be efficacious in acute or chronic ITP, IVIgG has been used increas­ingly for the treatment of patients who do not have a classic humoral antibody deficiency syndrome­particularly at higher doses, in the treatment of a wide range of autoimmune disorders ( 1~ 18). It is difficult to combine the clinical effects with a mul­titude of in vitro observations to explain the mech­anism of IVIgG action. Postulated mechanisms of action include blockade of cell surface IgG recep­tors, suppression of autoantibody production, and/ or interference in the binding of autoantibod­ies to target cells. IVIgG has also been rationally employed in the prevention of infection in preterm neonates and to treat intractable seizures, chronic inflammatory demyelinating polyneuropathies, atopic conditions with IgG subclass deficiency, and myasthenia gravis ( 19- 24). We only became acquainted with our patient late in the course of his illness, when his failure to grow and delayed puberty were obvious and his previous experience with an extremely slow taper from prednisone had been repetitively unsuccess­ful. At the time of his referral, there was no sub­stantiated evidence for the pathogenesis of his chronic optic neuritis. Apart from the initial trans­verse myelitis, there was no evidence of neurologic JClin Neuro- ophthalmol, Vol. 11, No. 4, 1991 244 L. P. FROHMAN ET AL. disease outside the visual system, and all labora­tory findings ( with the exception of IgG subclass 2 and 3 deficiency) were normal. Neither the cause nor the effect of his IgG subclass deficiency are clear from the evidence available to us. The atyp­ical steroid- dependency directs attention to the possibility of an underlying immunologic and in­flammatory disorder. Subclass deficiencies may be owing to a congen­ital syndrome or may be secondary to diseases or drugs which mediate excessive loss, reduced syn­thesis, or hypercatabolism of immunoglobulins ( 25). It is conceivable that this patient had an un­detected congenital deficiency, since IgG subclass deficiency and abnormal IgG subclass distribution do not always present with clinical symptoms, and asymptomatic subjects free of clinical illness or in­fection are occasionally discovered with negligible IgG subclass levels ( 26). In IgG subclass deficiency, depending on the severity of the defect, the total serum IgG may be normal, as in our patient, or decreased. Serum levels of IgM and IgA are typi­cally normal. Complete blood counts, sedimenta­tion rates, and radiologic findings are usually nor­mal. When manifested clinically, IgG subclass de­ficiency diseases are commonly associated with mucosal inflammatory processes; invasive disease is a clinical sign of a more significant impairment found in certain autoimmune disorders ( 26). Alter­natively, ( as in our patient) the humoral deficiency may have arisen during the course of long- term steroid therapy. In Sonderstrom's experience, treatment with corticosteroids did not affect over­all IgG levels, but IgG2 and IgG3 were reduced, which may be the primary cause of the subclass deficiency in our patient ( 27). Neurological abnormalities associated with hu­moral immunodeficiencies ( most commonly IgA) include myasthenia gravis, diphenylhydantoin treatment of epileptic patients, children with sei­zure disorders, and ataxia- telangiectasia ( 28- 31). However, a detailed analysis of IgG subclasses was only performed in one study revealing a deficiency of IgG2 in ataxia telangiectasia ( 32). Most patients with IgG subclass deficiency im­prove spontaneously or with conservative treat­ment; all patients respond to antibody replacement therapy with gamma globulin by a clearing of their symptoms. Before IVlgG became available, the usual form of therapy was intramuscular adminis­tration of gamma globulin. With intramuscular for­mulations, some patients develop symptoms of di­aphoresis, tachycardia, and hypotension thought to be mediated by aggregates in the IgG prepara- .1. 1j'Jntaf~ e of easy and rapid 1Clin Neure>- ophthalmol. Vol. 11, No. - I ) administration of large amounts of antibody with few side effects and little discomfort, and it is free of risk of transmission of infectious agents, includ­ing human immunodeficiency virus ( HIV) ( 13). The incidence of adverse reactions associated with IVlgG is reported by the manufacturers to be in the range of 1- 15%, usually less than 5%. Most of these reactions are mild and self- limited. Severe reactions may occur very infrequently and usually do not contraindicate further IVlgG therapy. Ad­verse reactions include pyrogenic responses marked by high fever and systemic symptoms; mi­nor systemic reactions with headache, myalgia, fe­ver, chills, lightheadedness, nausea, vomiting; va­somotor and/ or cardiovascular manifestations marked by changes in blood pressure and tachy­cardia, occasionally associated with shortness of breath and chest tightness; and hypersensitivity and anaphylactic reactions. Frequency of reactions are correlated with rate and volume of infusion. Seriously ill patients with compromised cardiac function may be at an increased risk of vasomotor or cardiac complications. Anaphylactic reactions are induced by anti- IgA and can occur in individ­uals who have a total absence of IgA. These reac­tions are extremely rare in panhypogammaglobu­linemia patients, but are more common in patients with subclass deficiencies. Neither HIV nor hepa­titis infection has been transmitted to recipients of products currently licensed in the United States. The various IVlgG are manufactured from large donor pools whose plasma has been tested and found negative for hepatitis B surface antigen and HIV. The mechanism by which gamma globulin aided recovery of this chronic bilateral optic neuritis is not clear. However, it is incontrovertible that the patient had required 3 years of chronic steroid sup­pression to prevent recurrence of optic neuritis, and this abated simultaneously with his treatment with gamma globulin. We conclude that patients with recurrent steroid- dependent optic neuritis should be tested for dysgammaglobulinemia, and if a deficiency is detected, IVlgG may be an alter­native to traditional therapeutic modalities. Acknowledgment: This study was supported by grants from the Fight for Sight- Research Division of the National Society to Prevent Blindness, Fund for the New Jersey Blind, Lions' Eye Research Foundation of New Jersey, and Research to Prevent Blindness, Inc. REFERENCES 1. Jabs DA, Miller NR, Newman SA, Johnson MA, and Stevens MB. Optic neuropathy in systemic lupus ery­thematosus. Arch Ophthalmol 1986; 104: 564- 8. DYSGAMMAGLOBULINEMIA 245 2. Nikoskelainen E. Symptoms, signs and early course of op­tic neuritis. Acta OphthalmoI1975; 53: 254- 71. 3. Scott GI. Neuromyelitis optica. Am / Ophthalmol 1952; 35: 755- 64. 4. Kupersmith MJ, Burde RM, Warren FA, Klingele TG, Frohman LP, Mitnick H. Autoimmune optic neuropathy: evaluation and treatment. / Neurol Neurosurg Psychiatry 1988; 51: 1381~. 5. Fleet WS, Watson RT. Autoimmune optic neuritis: a poten­tially treatable form of visual loss. Ann Ophthalmol 1986; 18: 144- 6. 6. Bielory L, Dong Z, Yip P, Frohman L. Anticardiolipin an­tibody ( ACA- Ab) binding to human optic nerve. Clin Res 1989; 37: 855a. 7. Frohman L, Bielory L, Warren F, Bystryn J, Kupersmith M. Skin biopsies in the evaluation of atypical optic neuropa­thies. Invest Opthalmol Vis Sci 1991; 32: 951( 1390- 16a). 8. Lubow M, Adams L. The changing management of acute optic neuritis. In Smith JL, ed. Neuro- ophthalmology. Sympo­sium of the University of Miami and the Bascom Palmer Eye Institute. St Louis, CV Mosby, 1972; 6: 44- 50. 9. Beck RW. The optic neuritis treatment trial. Arch Ophthalmol 1988; 106: 1051- 3. 10. Thirkill CE, Fitzgerald P, Sergott SC, Roth AM, Tyler NK, Keltner JL. Cancer associated retinopathy ( CAR syndrome) with antibodies reacting with retinal, optic- nerve, and can­cer cells. N Engl / Med 1989; 3231: 1589- 94. 11. Stites DP, Rodgers RPc. Clinical laboratory methods for detection of antigens and antibodies. In: Stites DP, Stobo JD, Wells lV, eds. Basic and clinical immunology. 6th ed. Nor­walk, CN, Appleton & Lange, 1987: 241-& 4. 12. Stiehm ER, Ashida E, Kim KS, Winston OJ, Haas A, Gale RP. Intravenous immunoglobulins as therapeutic agents. Ann Intern Med 1987; 107: 367- 82. 13. National Institutes of Health intravenous immunoglobulin con­sensus statement. NIH Consensus Development Conference, 1990 ( May 21- 23), 8: 5, 3- 18. 14. Imbach P, d'Apuzzo V, Hirt A, et al. High dose i~ travenous gammaglobulin for idiopathic thrombocytopenIc purpura in childhood. Lancet 1981; 1: 1228- 31. 15. Schwartz SA. Intravenous immunoglobulin ( IVIG) for the therapy of autoimmune disorders. / Clin Immunol 1990; 10: 81- 9. 16. McVerry BA, Spearing R, Smith A. SLE antico~ gulant: tran­sient inhibition by high dose immunoglobulm mfuslOns. Br / HaematoI1985; 61: 579- 80. 17. Leickly FE, Buckley RH. Successful treatment of autoim-mune hemolytic anemia in common variable immunodefi­ciency with high- dose intravenous gamma globulin. Am / Med 1987; 82: 159~ 2. 18. Savery F. Intravenous immunoglobulin treatment of rheu­matoid arthritis- associated immunodeficiency. elm Ther 1988; 10: 527- 9. 19. Pahwa RN. New and controversial uses of intravenous gamma- globulin. Pediatr Infect Dis / 1988; 7( suppl): 3~. 20. Berlit P. Immunoglobulin therapy in neurologic diseases. Klin Wochenschr 1989; 67: 967- 70. 21. Aarli JA. Immunoglobulins in epilepsy. Springer Semin Im­munopathol 1985; 8: S- 27. 22. Van Doorn PA, Vermeulen M, Brand A, Mulder PGH, Busch HFM. Intravenous gammaglobulin treatment in pa­tients with chronic inflammatory demyelinating polyneu­ropathy: clinical and laboratory associated characteristics associated with improvement. Arch NeuroI1991; 48: 217- 20. 23. Bjorkander J, Bake B, Oxelius VA, Hanson LA. Impaired lung function in patients with IgA deficiency and low levels of IgG2 and IgG3. N Engl / Med 1985; 313: 720- 4. 24. Asura EL et al. Effects of repeated doses of intravenous immunoglobulin in myasthenia gravis. Am / Med Sci 1988; 295: 438- 42. 25. French MAH. Serum immunoglobulins in disease. Diagno­sis and management. In: French MAH, ed. Immunoglobulins in health and disease. Norwell, MA: MTP Press, 1988: 123- 42. 26. Hammarstrom L, Smith ClE. Immunoglobulin isotype di­versity and its functional significance. In: French MAH, ed. Immunoglobulins in health and disease. Norwell, MA: MTP Press, 1988: 31- 53. 27. Soderstrom T, Soderstrom R, Andersson R, Lindberg J, Hanson LA. Factors influencing IgG subclass levels in se­rum and mucosal secretions. In: Skvaril F, Morrell A, Perret B, eds. Clinical aspects of IgG subclasses and therapeutic impli­cations. Basel, Karger: 1988: 236- 43. 28. Behan P, Simpson JA, Behan WM. Decreased serum IgA in myasthenia gravis. Lancet 1976; 1: 593- 4. 29. Seager J, Wilson J, et al. IgA deficiency, epilepsy and phe­nytoin treatment. Lancet 1975; 2: 632- 5. 30. Strober W et al. Immunoglobulin metabolism in ataxia­telangiectasia. / Clin Invest 1968; 47: 1905. 31. Schwartz SA, Gordon KE, Johnston MV, Goldstein GW. Use of intravenous gammaglobulin in the treatment of sei­zure disorders. / Allergy Clin ImmunoI1989; 84: 603- 7. 32. Oxelius VA, Berkel AI, Hanson LA. IgG2 deficiency in ataxia telangiectasia. N Engl / Med 1982; 306: 51S- 7. J Clin Neuro- ophthalmol, Vol. 11, No. 4, 1991