Case Study: An Infection-Triggered, Autoimmune Subtype of Anorexia Nervosa

Case Study: An Infection-Triggered, Autoimmune Subtype of Anorexia Nervosa MAE S. SOKOL, M.D.,

AND

NICOLA S. GRAY, B.S.

ABSTRACT Objective: Certain cases of anorexia nervosa (AN) may be similar to the recently described subtype of childhood-onset obsessive-compulsive disorder hypothesized to be one of the pediatric infection-triggered autoimmune neuropsychiatric disorders (PITANDs). Method: Three clinical cases are reported. The first patient is a 12-year-old boy whose AN worsened acutely after a group A

~-hemolytic

streptococcal (GABHS) infection. His symptoms were alleviated after antibiotic

treatment. Two other patients with possible PITANDs-related AN are described. Results: An infection-triggered process may contribute to the pathogenesis of a subtype of AN. Conclusions: Future research is needed to explore the nature of PITANDs and their relationship with AN. J. Am. Acad. Child Ado/esc. Psychiatry, 1997, 36(8):1128-1133. Key Words: anorexia nervosa, autoimmunity, eating disorders, obsessive-compulsive disorder, pediatrics, streptococcal infections.

A subtype of obsessive-compulsive disorder (OCD) has been postulated to be triggered via an autoimmune process in which antibodies directed against bacteria or viruses cross-react with basal ganglia neurons (Allen et al., 1995; Swedo, 1994). This has been referred to as pediatric infection-triggered autoimmune neuropsychiatric disorders (PITANDs). In certain cases of PITANDs, the pathogen is believed to be group A ~-hemolytic streptococcus (GABHS). This is referred to as pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS). To date, workers at the National Institute of Mental Health (NIMH) have evaluated and treated 50 cases of possible PANDAS and are conducting a double-blind, placebo-controlled trial of penicillin as prophylaxis against PANDAS (Perlmutter et aI., 1996). Evidence with respect to phenomenology, comorbidity, neurotransmitters, and CNS functional metabolism

Accepted/tl1l1l11ry 24, 1'J'J1. Dr. Sokol is ",ith the Ellillg Disorders l'rogmlll, !l1f11llillga Clillic, Topek'l. KS. Ms. (,'my is il lIIedic,t! stl/delll til the Vllillersity of Pittsbl/rgh School of Medicille. The ill/thors tlJilllk Mr. SCOII BI/rga, Drs. Milrjorie Gm'ey, Fd"'ilrd Kilplilll, Willter Kilye, SWilll l'er/mllller. illld SWilll Suwlo. Reprilll reql/ests 10 Dr. Sokol. Menllillger. 1'0. Box 82'J. lopekil. KS 66601 . telepholle: ('J13! 350-5000.. fitx: ('J13J 350-4264.. e-Illtlil.. soko{,m@)menIlillger.edu 0890-8S67/97/j608-1128/$O..\OO/OiD ]997 by the American Academy of Child and Adolescent Psychiatry.

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supporting the idea that OCD and anorexia nervosa (AN) are related (Jarry and Vaccarino, 1996; Kaye et al., 1991, 1992), along with these encouraging preliminary results in OCD treatment, led us to consider a similar approach in AN. We hypothesize that there is a subtype of AN which is similar to the PANDAS subtype of OCD. Future research is needed to determine whether this type of AN may respond to acute and prophylactic treatment with antibiotics and immunological agents. In reviewing the literature, we found no investigations that address the issue of possible infectious or autoimmune etiology or risk factors for eating disorders. Here we report on three patients with AN in whom there is a possible PITANDs etiology.

BACKGROUND Despite current treatments, the prognosis of AN remains poor, with a high relapse rate and prolonged morbidity. Indeed, AN has one of the highest rates of morbidity and mortality of any psychiatric illness. Most studies report mortality rates of about 5% in the first 5 to 8 years of follow-up, and between 13% and 20% after 20 years (Crisp et aI., 1992). Prevalence studies among females in late adolescence and early adulthood have found rates of 0.5% to 1.0% for AN, with a significant increase of incidence in the past two decades. Swedo's group at the NIMH (Allen et al., 1995) identified a subgroup of children with episodic OCD or tic

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disorder in whom symptom exacerbation was preceded by GABHS or other infection and appeared to be mediated through antineuronal antibodies. In all four of these cases of possible PITANDs, there was a dramatic onset or worsening of clinically significant symptoms followed by a slow waning over a period of months, a pattern strikingly similar to the course of Sydenham's chorea. Two of the patients were treated with plasmapheresis, one with intravenous immunoglobulin and one with immunosuppressive doses of prednisone. Of the two patients with positive throat cultures for GABHS pharyngitis, one received prophylactic penicillin after plasmapheresis and the other entered a doubleblind study of penicillin versus placebo following intravenous immunoglobulin. Each patient had a clinically significant response. It was hypothesized that susceptible individuals, often identified by a lymphocyte B 08/17 marker associated with rheumatic fever (Khanna et al., 1989), developed autoantibodies which ostensibly attack cerebral basal ganglia, leading to neuropsychiatric symptoms. Since then, the NIMH group has described 50 cases of possible PANDAS (Perlmutter et al., 1996) and reported on 27 children with PANDAS among whom 85% were positive for 08/17 (Swedo et al., 1997). Systematic investigations by Swedo et al. have demonstrated that obsessive-compulsive symptoms occur in more than 70% of children affected by Sydenham's chorea and that these symptoms are indistinguishable from those of classic OCD (Swedo et aI., 1994). The numbers of children with Sydenham's chorea studied were 23 (Swedo et aI., 1989a) and 11 (Swedo et al., 1993). In addition to choreic movements, many Sydenham's patients have ticlike, adventitious movements (Swedo et aI., 1989a). Furthermore, in a study of children and adolescents (n = 54) presenting with childhood-onset OCD, one third had choreiform movements detected by structured neurological examination, and approximately 60% had a history of motor and/or vocal tics (Swedo et aI., 1989b). Sydenham's chorea is the prototype for the syndrome of antineuronal antibody-mediated CNS dysfunction (Swedo, 1994). In this variant of rheumatic fever, antibodies directed against GABHS are thought to crossreact with neuronal cells and cause motor and behavioral disturbances (Husby et al., 1976). These antibodies are different from those found in systemic lupus erythematosus and other autoimmune disorders.

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The nature of the relationship between anti neuronal antibodies and neuropsychiatric symptoms is unknown. However, the antibodies appear to recognize cellular components within the basal ganglia, and basal ganglia dysfunction has been implicated in both Sydenham's chorea and OCD (Swedo et al., 1993, 1994). It is interesting that longitudinal studies reveal a direct correlation between antineuronal antibody titers and symptom severity for those children with episodic OCD (Swedo et al., 1994). Extrapolating from the American Heart Association's (Dajani et al., 1995) guidelines for the use of penicillin to prophylactically treat children with rheumatic heart disease, a double-blind, placebo-controlled trial of penicillin for the prevention of OCD or tic disorder exacerbation in children with GABHS infections is under way at the NIMH (Perlmutter et al., 1996). Evidence supporting the idea that OCD and AN are related led us to consider a similar approach in AN. Here we report on the possibly effective use of antibiotic treatment for a 12-year-old boy who experienced severe worsening of anorexic symptoms after GABHS infection. Two other cases of anorexic adolescents who have clinical presentations consistent with PITANDs are also reported. Diagnoses were based on clinical assessments by two psychiatrists using DSM-/V criteria (American Psychiatric Association, 1994). All three patients met criteria for AN, restricting type. They refused to maintain a minimal body weight of at lease 85% of average expected body weight (ABW) for their age and height, had intense fear of gaining weight, and believed they were overweight, despite objective evidence to the contrary. Their self-esteem was overly influenced by body weight and exercise level. They denied the seriousness of malnutrition and its medical complications. None of the patients engaged in binge eating, purging behavior (vomiting or laxative, enema, or diuretic misuse), or substance abuse. All weights were calculated using standard pediatric growth chans (Hamill et al., 1979). The three patients met all but one of the criteria required for the diagnosis of OCD: since the content of the obsessions and compulsions was exclusively related to another mental disorder, in this case, an eating disorder, a diagnosis of OCD could not be given. However, their recurrent obsessions about food and compulsive exercise caused them severe distress and functional impairment.

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stage was III to IV. Laboratory test results were normal except that streptococcal infection workup (Peter, 1996) revealed a high anti-deoxyribonuclease B (antiDNase B) titer of 1:340 (normal < 1: 170 for age 7 to 17 years; this is suggestive, but not proof, of a recent group A streptococcal infection), an elevated antistreptolysin 0 (ASO) level of 1:400 (normal < 1: 170), negative antinuclear antibody titer, and negative throat culture. The patient underwent a psychiatric evaluation, and conventional eating disorder treatment, including refeeding, was started. A 7-day course of amoxicillin, 250 mg orally t.i.d., was prescribed because of moderately severe sinusitis. Four days after admission, Ruoxetine, 10 mg/day, was prescribed for control of eating disorder symptoms. Two days after admission, the patient's behavior began to improve steadily. He found it easier to refrain from exercise, was less anxious, and became much more comfortable with eating. Seven days after admission, the amoxicillin course was completed, and 3 to 4 days later, the patient's behavior became much worse. He was found in the bathroom, pounding on his injured foot as he exercised vigorously. Fifteen days after admission, the patient was started on a second course of amoxicillin, 250 mg t.i.d. for 10 days, for the treatment of infection. Three days later, his behavior began to improve again. The patient has continued to take amoxicillin, 250 mg b.i.d., for infection prophylaxis. He continued to improve for the rest of his month-long hospitalization and for the 3 months since discharge. His 9-year-old brother said, "My brother has been gone for the past year and he's finally back." One month after hospital discharge, the following laboratory results were obtained: anti-DNase B = 1:340 V; ASO titer = 400 IV; negative throat culture; negative antinuclear antibody, Lyme, and Mycoplasma titers.

CASE STUDIES Patient 1

Patient 1 is a 12-year and 8-month old boy who presented with a lO-month history of symptoms of acute onset consistent with a severe eating disorder, including weight loss, compulsive overexercising to the point of self-injury, severe restriction of food intake, irritability, social withdrawal, sadness, and anxiety, requiring psychiatric hospitalization on an eating disorders unit. He lost 30 to 40 pounds, dropping from about 115% ABW to 74% ABW. He became afraid to eat most foods, especially fats and liquids. He developed an intense fear of gaining weight and insisted he was overweight, despite objective evidence to the contrary. The patient spent most of his waking hours exercising and obsessively thinking about weight, food, and exercise. While he never binged or purged, he frequently chewed and spit out food. His school grades dropped from superior to average. The patient and his parents report that his symptoms increased dramatically 4 months before admission. He increased his exercise, engaging in numerous physical activities for several hours each day. He increased his running to 60 miles per week, causing a stress fracture of his right fifth metatarsal bone. He continued to run on the injured foot for 2 months despite his parents' best efforts and warning from the orthopedist that this could cause permanent damage to the bone's growth plate. The patient's only significant premorbid psychiatric symptoms were mild motor and vocal tics for brief periods throughout his childhood, possibly starting at about age 3 years. His medical history is significant for an untreated severe upper respiratory tract infection 5 months prior to admission and 1 month prior to the severe exacerbation of symptoms. The infection lasted about 2 weeks, with thick yellow sputum, in the patient and all immediate family members. The patient's history is also significant for an adenomatous variant of Wilms' tumor in the right kidney at age 9 years (treated by right nephrectomy), pneumonia, and retrovirus infection at age 13 months; chronic ear infections from infancy to 2 years of age; mycoplasma pneumonia at age 3 years; frequent strep throat starting at age 3 years; and mononucleosis at age 8 years. On admission, physical examination results were normal except for moderately severe sinusitis and mild choreiform movements of all four extremities. Tanner

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Patient 2

Patient 2 is a girl who was evaluated at age 14 years and 9 months. She had a severe Epstein-Barr virus infection at age 13 years and was bedridden for 6 months. She had no history of an eating disorder, OeD, tics, or any psychiatric symptoms. She developed postinfectious autoimmune migratory polyarthritis due to Epstein-Barr virus at age 13 years and 8 months. She went on a diet at this time and developed obsessive con-

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cerns about eating and being overweight. Antinuclear antibody titer was 1:320, with a diffuse pattern. ASO titer, anti-DNase B, and throat culture were negative, indicating that streptococcal infection was extremely unlikely (E. Kaplan, personal communication, January 15, 1997). At age 13 years and 11 months, at the time of an exacerbation of the patient's arthritis, a sudden increase in the patient's eating disorder symptoms occurred, including compulsive overexercise, caloric restriction, and obsessive thoughts that she was overweight. The patient lost about 40 pounds in the next 4 months. Her weight decreased from about 100% ABW to 65% ABW She denied bingeing, purging, and the use of laxatives, diuretics, and diet pills. The patient's eating disorder and arthritis decreased in parallel during the next 11 months with conventional treatment. Both conditions went into remission shortly after the beginning of this evaluation, and no further treatment was needed. Patient 3

Patient 3 is a 16-year-old boy whose mild AN was in remission at the time of evaluation. Starting about 6 months earlier, he had a series of upper respiratory tract infections, sudden onset of obsessive symptoms, and failure to gain expected weight as he grew taller. His weight decreased from average to about 83% ABW 1 month before evaluation. His obsessive symptoms included overconcern with the content of his food, obsessions about "dead animals on plates," and intense fear of gaining weight. On evaluation, anti-DNase B was moderately elevated at 1:340. Throat culture, ASO titer, and antinuclear antibodies were negative. The patient had no history of tics or frank obsessions or compulsions, but he had always had an obsessive style. He had many upper respiratory tract infections in childhood, with many throat cultures positive for GABHS, even after antibiotic treatment. Starting 1 month prior to this evaluation, and during the next few months, the patient's eating disorder and obsessions progressively went into remission. No treatment was needed. DISCUSSION

These cases raise the possibility that a subgroup of AN, characterized by a postinfectious acute onset, or

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significant worsening of clinical symptoms, may exist. As in the PANDAS subtype of OCD, such cases might be clinically distinguishable by a pediatric onset; a sudden onset of clinically significant symptoms and/or a pattern of sudden, recurrent symptom exacerbations and remissions; increased symptoms that are pervasive and do not occur exclusively during stress or illness; and evidence of an antecedent or concomitant infection (Allen et aI., 1995). The possibility of a PANDAS subtype of AN also raises some interesting issues with regard to the management of children presenting with sudden onset or acute worsening of anorectic symptoms. It suggests that infectious disease history needs to be evaluated in relation to eating disorder symptoms. Currently, no such recommendations exist in the practice guidelines for eating disorders (American Psychiatric Association, 1993; Bryant-Waugh et aI., 1992). Although it may be premature to conclude that AN is a variant of OCD, there is evidence supporting the idea that these two disorders are related. There is a high level of comorbidity ofOCD and AN, both in individuals and in their family members (Halmi et aI., 1991; Rasmussen and Eisen, 1989), even after weight recovery (Kaye et aI., 1992, 1993; Study Group on Anorexia Nervosa, 1995). OCD patients also appear to have prominent eating disorder symptoms (Hsu et al., 1993; Pigott et aI., 1991). Some of the features of AN are, in fact, part of the criteria sets for OCD in DSM-IV (American Psychiatric Association, 1994). These include recurrent obsessions and compulsions related to food, obsessive overconcern with body shape and size, and compulsive overexercise. Neurobiological evidence indicates elevated serotonin functions in classic symptoms ofOCD (lnse!, 1992; lnsel et aI., 1985; Jarry and Vaccarino, 1996; Kruesi et aI., 1990; Thoren et aI., 1980; Zohar et aI., 1988) and AN (Kaye et aI., 1991). Preliminary evidence from positron emission tomography scans suggests increased caudate functional metabolism in AN (Herholz et aI., 1987) and OCD (Baxter, 1992). This is consistent with Giedd and colleagues' (1996) finding of changes in basal ganglia volume, particularly of the caudate and globus pallid us, in relation to obsessive-compulsive symptom severity in a 12-year-old boy with PANDAS OCD. After plasmapheresis, symptoms decreased (including compulsive overexercise), and magnetic resonance imaging showed a decrease in

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Crisp AH. Callender JS. HOlick C. Hsu 1.K (1992), Long-term morrality in anorexia nervosa: a 20-year follow-up of the St George's and Aberdeen cohorl. Br J P~ychiarry 161: 104-107 Dajani A. Tauben K, Ferrieri P. Peter G. Shulman S (Committee on Rheumatic Fever, Endocarditis. and the Kawasaki Disease Council on Cardiovascular Disease in the Young, the American Heart Association) (1995), Treatmelll of aCute streptococcal pharyngitis and prevention of rheumalic fever: a stalement for health professionals. Prdiatrics 4:758-764 Giedd IN, Rapoport JL, Leonard HL, Richter D, Swedo SE (1996), Case study: acute basal ganglia enlargement and obsessive-compulsive sympIOms in an adolescent boy. JAm Acad Child Adolrsc Psychiatry

basal ganglia volume. This patient subsequently developed AN (J.N. Giedd, personal communication, October 23, 1996). Conclusions The need for new and more effective treatments for AN, along with the evidence supporting the idea that AN may be related to OeD, led the authors to hypothesize that a pediatric, infection-triggered, autoimmune subtype of AN may exist, similar to the PANDAS subtype of oeD. It will be important to further investigate the possible existence of this subtype of AN, not only because these patients may benefit from careful monitoring for GABHS and other infections, but for the potential benefit that new treatment options might offer patients. Early intervention and prophylactic treatment could, theoretically, limit the immune response and potentially thwart the onset or worsening of AN in these individuals. The possibility of weight loss due to autoimmune processes may also have implications for the understanding of cachexia that can accompany chronic autoimmune disease, a phenomenon that has never been well explained. It is suggested that in all pediatric cases of AN, particularly those with sudden onset or exacerbation of symptoms, it may be beneficial to incorporate in the initial workup a detailed infectious disease history, a throat culture, and streptococcal serological studies (anti-DNase Band ASO titers). Antibiotics, immunological treatments, and a vaccine under investigation for rheumatic fever (Pruksakorn et a!', 1994) should be investigated as potentially beneficial treatment for a subgroup of anorectics. Future research is needed to develop new approaches for the treatment and prevention of AN.

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Arch Gm Psychiatry 49:739-744 Insel TR, Mueller EA, Ahrman I, 1.innoila M, Murphy DL (1985), Obsessive-compulsive disorder and serotOnin: is there a connection' BioI Psychiatry 20: 1174-1188 Jarry JL, Vaccarino FJ (19%), Eating disorder and obsessive-compulsive disorder: neurochemical and phenomenological commonalilies. J Psychiatry N"'rosci 121 :.~6-48 Kaye WH, Gwinsman HE, George DT, Ebert MH (1991), Altered serotonin activity in anorexia nervosa after long-term weight restoration: does elevated cerebrospinal fluid 5-bydroxyindoleacetic acid level correlale with rigid and obsessive behavior? Arch Gm P~ychiatry 48:556-562 Kaye WH, Weltzin TE, Hsu LG (1993), Relationship between anorexia nervosa and obsessive and compulsive behaviors. Psychiatr Ann 23:.~65-.H3

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J Fating Disord 12:57-62 Khanna AK, Buskirk DR, Williams RC Jr et al. (1989), Presence of a nonH LA B cell antigen in rheumalic fever patiellls and lheir families as defined by a monoclonal antibody. J Gin III/Irs/ 83: 1710-1716 Kruesi MJ, Rapoport JL, Hamburger 5 et al. (1990). Cerebrospinal fluid monoamine metabolites, aggression, and impulsivity in disruptive behavior disorders of children and adolescents. Arch Grn Psychiatry 47:419-426 Perlmutter SJ, Leonard HS, Garvey MA et oIl. (1996), The phenomenology of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Poster presentation at the 43rd Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Philadelphia Peter JB (1996), Usr and Imrrpmatiolt 0/ Trsts ill Illftetiotls Disrau. Santa Monica, CA: Specialty Laboratories. PI' 272-274 Pigott TA, Altemus M, Rubenstein C:S et al. (1991), Symptoms of eating disorders in patients wilh obsessive-compulsive disorder. Am J Psychiatry 148:1552-1557 Pruksakorn S, Currie B, Brandt E et al. (1994), Towards a vaccine for rheumatic fever: identification of a conserved larget epitOpe on M protein of group A streptococci. Lal/crt 344:639-642 Rasmussen SA, Eisen JL (1989), Clinical features and phenomenology of obsessive-compulsive disorder. Psychiatr Anll 19:67-7.~

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