Author's Accepted Manuscript
Presence of Anti-brain Antibodies in ObsessiveCompulsive Disorder Secondary to Pineal Gland Germinoma: a Case Report Weiguo Zhu M.D., Ph.D., Karl S. Burgoyne M. D., Ira M. Lesser M.D.
PII: DOI: Reference:
S0033-3182(14)00075-9 http://dx.doi.org/10.1016/j.psym.2014.05.001 PSYM458
To appear in:
Psychosomatics
Cite this article as: Weiguo Zhu M.D., Ph.D., Karl S. Burgoyne M.D., Ira M. Lesser M.D., Presence of Anti-brain Antibodies in Obsessive-Compulsive Disorder Secondary to Pineal Gland Germinoma: a Case Report, Psychosomatics, http://dx. doi.org/10.1016/j.psym.2014.05.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Presence of Anti-brain Antibodies in Obsessive-Compulsive
Disorder Secondary to Pineal Gland Germinoma: a Case Report Authors: Weiguo Zhu, M.D., Ph.D. Karl S Burgoyne, M.D. Ira M Lesser, M.D. Affiliation: Department of Psychiatry Harbor-UCLA Medical Center David-Geffen School of Medicine University of California, Los Angeles, Key words: obsessive-compulsive disorder; brain; tumor; autoantibodies; pineal gland Corresponding author: Dr. Weiguo Zhu Department of Psychiatry Harbor-UCLA Medical Center 1000 W Carson Street Torrance, CA 90509 Tel: 310-222-3103 Fax: 310-222-1815 E-mail: [email protected]
1
Abstract: Symptoms of obsessive-compulsive disorder (OCD) have been found to be associated with brain neoplasms. We report a case of OCD secondary to a brain pineal gland germinoma. The patient is a 23-year-old male with no past history of medical and psychiatric disorders. He had an onset of OCD symptoms after achieving radiological remission of the brain tumor. A serum sample from the patient was tested positive for the presence of anti-brain antibodies. Brain specific proteins of 43 kd and 45 kd were identified as target antigens using western blotting analysis.
Indirect immunofluorescent staining showed nuclear plasma as well as
nucleolar staining patterns. We present this case which may illustrate the autoimmune aspects of pathophysiology in OCD symptoms secondary to brain tumor.
Introduction: Obsessive-compulsive disorder (OCD) is a neuropsychiatric illness characterized by the experience of recurrent, intrusive, and distressing thoughts, images, and urges to action (1). It was considered a rare disorder, but new data have revealed that it is, in fact, a relatively common illness, particularly in childhood and adolescence (2). and pathophysiology of OCD are not well understood.
The etiology
Various factors involving
psychosocial, genetic, neuroanatomic, and neurochemical factors have been identified (36). A subset of patients with pediatric onset OCD and tic syndrome (e.g. Tourette's syndrome) have a symptom onset or exacerbation associated with group A betahemolytic streptococcal (GABHS) infection (7-10). The term “pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections” (PANDAS) has been coined to describe those patients with evidence of recent group A beta hemolytic streptococcal infection. Numerous studies have reported the presence of anti-brain, anti-
2
neuron, and anti-basal ganglia antibodies in these patients (11-14).
Pavone et al.
reported a study showing that 64% of patients with PANDAS are positive for anti-basal ganglia antibodies, but only 9% were positive compared to the group with GABHS infection without PANDAS (15).
Swedo proposed an autoimmune model where
antibodies against GABHS have cross-reactions with specific brain antigens and result in movement disorder and OCD symptoms (16). The target antigens remain unknown; however, a number of studies have reported identification of some neuronal proteins at 40 kd, 60 kd, and 83 kd as common target proteins (15, 17-19). Limbic encephalitis is an inflammation of the limbic system, which includes the thalamus, hypothalamus, hippocampus and amygadala. It has been reported as paraneoplastic syndrome associated with malignancies in lung, ovary, breast, etc. (20). Antibodies targeting the oncoproteins have cross reactions with cellular components in brain resulting in neurological symptoms. A series of antigens have been identifies, such as Hu, Ma, Ri, voltage gated potassium channel etc. (21). More recently, Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been characterized (22). It has predominant psychiatric symptoms during early phase of the illness, such as delusions and hallucinations, and often leads patients to seek psychiatric evaluation and treatment. The presence of autoantibodies against NMDAR, particularly NR1 subunit, in both serum and cerebral spinal fluid of patients has led to the hypothsis of an autoimmune mediated NMDA dysfunction where autoantibodies alter the structure and function of the receptor. Effective treatment with immune modulators further supports the hypothesis of autoimmune mechanism of the disease.
3
There are a number of cases reporting the onset of OCD symptoms secondary to brain tumors (23-27). In other cases, the OCD symptoms occurred after the surgical removal of the tumor or after successful treatment with radiation and chemotherapy (2831). We report a patient who developed OCD symptoms after the successful treatment of a pineal gland germinoma with radiation. We demonstrate the presence of anti-brain antibodies in the serum of this patient, and discuss the possibility of a tumor-induced immune attack of brain tissue in the pathogenesis of OCD.
Case report: Mr. B is a 23-year-old, right-handed male, previously in good physical and mental health. Over a period of 3 months, he developed headaches, bi-temporal vision loss, generalized weakness and memory loss. On physical examination, he had a right IVth nerve palsy and signs suggestive of mid-brain pathology. A brain magnetic resonance image (MRI) scan demonstrated an enlarged pineal gland with a similar area of enhancement in the suprasellar cistern involving the optic chiasm and mammilliary body, and evidence of pituitary extension (Fig. 1). There was no involvement in nuclei of the basal ganglia or other brain regions. The diagnosis of germinoma was confirmed by biopsy. Mr. B was successfully treated with a course of cranial irradiation, and he began a regimen of pituitary hormone replacement therapy which included: Prednisone 5 mg, and Levothyroxine 75 μg daily, Desmopressin 10 μg twice a day, and Testosterone injection 400 mg every 4 weeks.
Approximately three months after achieving
radiological remission, he developed a preoccupation with germs and fears of contracting bacteria, which prompted him to begin washing his hand extensively. His symptoms of OCD included obsessions about his homework assignment and contaminations with
4
germs, performing certain senseless tasks over and over again, such as checking and making sure he takes medications, checking his homework, etc. On the YBOCS (YaleBrown Obsessive-Compulsive Scale) (32, 33), he scored 29 on a 0 to 40 scale indicates moderate severity of symptoms. He denied experiencing any OCD symptoms or other psychiatric symptoms prior to the onset of brain tumor. He has a negative family history of psychiatric illness.
Results: Prior to the psychiatric treatment, 10 ml of whole blood was obtained from the patient. Serum of the patient was used for the following analyses. Figure 2 shows the western blotting analysis using the patient’s serum as the primary antibody. Total proteins from a number of normal human tissues were separated by SDS-PAGE and transferred on to a nitrocellulose membrane. A pair of protein bands of approximately 43 kd and 45 kd were observed in normal human brain tissue. These proteins appear brain specific, since no positive bands at the similar molecular weight range were found in other normal human tissues: lung, heart, liver, and kidney. In addition, serum from a normal human subject was used as a negative control generated no signal (data not shown). There are strong reactions with the proteins at both 25 kd and 50 kd in all tissues tested, which are presumably the human immunoglobulin heavy and light chains. The anti-brain antibodies are IgG class, because the secondary antibody used as a detection agent is IgG specific. The immune reactivity can be detected at a dilution of 1:100. Thus, the patient serum contains antibodies specific to proteins extracted from normal human brain tissue.
5
In order to understand the subcellular localizations of the antigens, we also performed indirect immunofluorescent staining similar to ANA staining. The patient serum generates a positive staining with Hep2 epithelial cells. Figure 3 shows a staining pattern of fine nuclear plasma staining as well as nucleolar staining, suggesting that the antibodies may recognize components in the ribonuclear complex. The staining pattern of mitotic cells indicates no DNA binding activities. The signal can be detected with up to 1:320 dilution of the serum.
Discussion: Various neurological disorders are accompanied with symptoms of OCD, e.g. encephalitis, drugs, head trauma, brain tumors, and PANDAS. There are at least eight case reports documenting the association of OCD symptoms with either the progression of brain tumor or remission after surgical removal of tumor or radiation treatment (2331). Ward first reported three cases of transient feelings of compulsion caused by hemispheric lesions (23).
All three patients experienced episodic, short lasting
neuropsychiatric symptoms and neurological deficits.
Brain lesions in frontal lobe,
temporal lobe, basal ganglia and cerebellum were subsequently identified.
The
neuropsychiatric symptoms may represent partial seizures since all three cases showed epileptic activities in EEG studies. Interestingly, there are four cases reporting that OCD symptoms started after surgical removal of brain tumor or successful radiation treatment of brain tumors. Craven (31) presented a case of a 15 year-old female who developed acute psychosis and OCD symptoms fourteen months after successful treatment of a pineal germinoma.
Mordecai et al. reported that a 13 year-old female who had a
supresellar germinoma with basal ganglia involvement presented with OCD and
6
psychotic symptoms (26). Our patient shares many common clinical and radiological features with both of these cases, although he was not psychotic. Intriguingly, these patients had no experience of psychiatric symptoms either prior to the onset of brain tumor, or shortly after the treatment. In all cases, there was a symptom-free period followed by OCD symptoms without evidence of tumor relapse when the OCD symptoms developed. This suggests that there is a delayed effect resulting from either tumor or from the surgical or radiation treatment in the regions, such as basal ganglia, anterior cingulate and orbital-frontal cortex. An alternative explanation for developing OCD symptoms in this patient is the presence of anti-brain specific antibodies in patient serum. We hypothesize that the destruction of brain tumor during surgery and radiation allowed the debris to be released into the circulation where the immune system recognized either neoplastic components or normal brain proteins that are normally sequestered from the immune system. The activation of the immune system would result in autoantibody production and/or cytotoxic cellular attack of brain tissue, which then could cause brain dysfunction. The possibility of a tumor-induced immune attack on brain structures, analogous to the paraneoplastic neurologic syndrome (34-36), has not previously been entertained. Scheid et al. reported a case in which the OCD symptoms were the first signs in a patient having testicular cancer and anti-Ma2 positive paraneoplastic limbic encephalitis (37). Ma2 is a neuronal protein of 40 kd and anti-Ma2 antibody is thought to be induced by the testicular cancer and be involved in paraneoplastic encephalitis and neuropsychiatric symptoms.
On indirect immunofluorescent staining, anti-Ma2 generates a nucleolar
staining pattern, similar to what we found in this patient.
7
Anti-brain antibodies have been identified in sera of patients with PANDAS. The 40 kd, 60 kd, 83 kd proteins are reported as target antigens. Hoekstra et al. has recently identified the 60 kd heat shock protein as a common antigen in tic disorders (19). We identified brain specific proteins of 43 kd and 45 kd as the targets of anti-brain antibodies. These proteins appear to be localized in nuclear plasma and nucleoli. The identities of these proteins remain to be determined. It is quite intriguing if these proteins could be part of the NMDAR. Base on the cases so far reported, NR1 subunit of NMDAR is the most common target of autoantibodies in anti-NMDA encephalitis. The molecular weight of NR1 is approximately 115 kd. Therefore, it is unlikely that our patient serum contains antibody against NR1. In addition, the immunofluorescent staining pattern suggested an intracellular localization of the antigens in question. Future studies will be carried out to delineate the molecular identities of these proteins and the localization of these proteins in brain. Characterization of the biological functions of these proteins might provide insight into the pathophysiology of OCD.
Acknowledgments: We are grateful to Dr. C. Mark Mehringer, Department of Radiology, HarborUCLA Medical Center for assistance with radiology evaluation of the patient. We thank Dr. Samuel French, Department of Pathology, Harbor-UCLA Medical Center for laboratory technical support. We also thank Drs. Edmond Pi, Andrew Ho, and Robert Berthold for their helpful discussion and critical review of the manuscript.
Financial Disclosures: The authors reports no financial relationships with commercial interests.
8
References: 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington DC: Psychiatric Press 1994 2. Jenike MA: Obsessive-compulsive and related disorders: a hidden epidemic. N Engl J Med 1989; 321: 539-541 3. Bumpass ER, Knoll JL, III: Emotional factors in oculogyric crisis. J Nerv Ment Dis 1982; 170: 366-370 4. McKeon J, McGuffin P, Robinson P: Obsessive-compulsive neurosis following head injury. A report of four cases. Br J Psychiatry 1984; 144: 190-192 5. Ward CD: Encephalitis lethargica and the development of neuropsychiatry. Psychiatr Clin North Am 1986; 9: 215-224 6. Hymas N, Lees A, Bolton D, Epps K, Head D: The neurology of obsessional slowness. Brain 1991; 114 ( Pt 5): 2203-2233 7. Swedo SE, Rapoport JL, Cheslow DL, Leonard HL, Ayoub EM, Hosier DM et al: High prevalence of obsessive-compulsive symptoms in patients with Sydenham's chorea. Am J Psychiatry 1989; 146: 246-249 8. Leonard HL, Swedo SE: Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Int J Neuropsychopharmacol 2001; 4: 191-198 9. Snider LA, Swedo SE: Post-streptococcal autoimmune disorders of the central nervous system. Curr Opin Neurol 2003; 16: 359-365 10. Swedo SE, Leonard HL, Rapoport JL: The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) subgroup: separating fact from fiction. Pediatrics 2004; 113: 907-911 11. Kiessling LS, Marcotte AC, Culpepper L: Antineuronal antibodies: tics and obsessive-compulsive symptoms. J Dev Behav Pediatr 1994; 15: 421-425 12. Singer HS, Giuliano JD, Hansen BH, Hallett JJ, Laurino JP, Benson M et al: Antibodies against human putamen in children with Tourette syndrome. Neurology 1998; 50: 1618-1624
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13. Muller N, Kroll B, Schwarz MJ, Riedel M, Straube A, Lutticken R et al: Increased titers of antibodies against streptococcal M12 and M19 proteins in patients with Tourette's syndrome. Psychiatry Res 2001; 101: 187-193 14. Black JL, Lamke GT, Walikonis JE: Serologic survey of adult patients with obsessive-compulsive disorder for neuron-specific and other autoantibodies. Psychiatry Res 1998; 81: 371-380 15. Pavone P, Bianchini R, Parano E, Incorpora G, Rizzo R, Mazzone L et al: Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection. Pediatr Neurol 2004; 30: 107-110 16. Snider LA, Swedo SE: PANDAS: current status and directions for research. Mol Psychiatry 2004; 9: 900-907 17. Wendlandt JT, Grus FH, Hansen BH, Singer HS: Striatal antibodies in children with Tourette's syndrome: multivariate discriminant analysis of IgG repertoires. J Neuroimmunol 2001; 119: 106-113 18. Church AJ, Cardoso F, Dale RC, Lees AJ, Thompson EJ, Giovannoni G: Anti-basal ganglia antibodies in acute and persistent Sydenham's chorea. Neurology 2002; 59: 227-231 19. Hoekstra PJ, Horst G, Limburg PC, Troost PW, van LN, de BA et al: Increased seroreactivity in tic disorder patients to a 60 kDa protein band from a neuronal cell line. J Neuroimmunol 2003; 141: 118-124 20. Dalmau J, Graus F, Rosenblum MK, Posner JB: Anti-Hu--associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine 1992; 71: 59-72 21. Vincent A1, Buckley C, Schott JM, Baker I, Dewar BK, Detert N et al: Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004; 127: 701-712
22. Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A et al: Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007; 61: 25-36
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23. Ward CD: Transient feelings of compulsion caused by hemispheric lesions: three cases. J Neurol Neurosurg Psychiatry 1988; 51: 266-268 24. Shuren JE, Flynn T, Fennell E, Crosson B: Insula and obsessive-compulsive disorder. Can J Psychiatry 1995; 40: 112 25. Peterson BS, Bronen RA, Duncan CC: Three cases of symptom change in Tourette's syndrome and obsessive-compulsive disorder associated with paediatric cerebral malignancies. J Neurol Neurosurg Psychiatry 1996; 61: 497-505 26. Mordecai D, Shaw RJ, Fisher PG, Mittelstadt PA, Guterman T, Donaldson SS: Case study: suprasellar germinoma presenting with psychotic and obsessivecompulsive symptoms. J Am Acad Child Adolesc Psychiatry 2000; 39: 116-119 27. Gamazo-Garran P, Soutullo CA, Ortuno F: Obsessive-compulsive disorder secondary to brain dysgerminoma in an adolescent boy: a positron emission tomography case report. J Child Adolesc Psychopharmacol 2002, 12: 259-263 28. Paradis CM, Friedman S, Hatch M, Lazar RM: Obsessive-compulsive disorder onset after removal of a brain tumor. J Nerv Ment Dis 1992; 180: 535536 29. Moriarty J, Trimble M, Hayward R: Obsessive-compulsive disorder onset after removal of a brain tumor. J Nerv Ment Dis 1993; 181: 331 30. Rogers MP, Mendoza AY: Development of obsessive-compulsive disorder after brain tumor surgery and radiation. Psychosomatics 1994; 35: 402-406. 31. Craven C: Pineal germinoma and psychosis. J Am Acad Child Adolesc Psychiatry 2001; 40: 6 32. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL et al: The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry 1989; 46: 1006-1011 33. Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR et al: The Yale-Brown Obsessive Compulsive Scale. II. Validity. Arch Gen Psychiatry 1989; 46: 1012-1016 34. Posner JB: Immunology of paraneoplastic syndromes: overview. Ann N Y Acad Sci 2003; 998: 178-186
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35. Darnell RB, Posner JB: Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003; 349: 1543-1554 36. Posner JB: Anti-neuronal antibodies in patients with cancer. Ann Neurol 2004; 56: 609-610 37. Scheid R, Voltz R, Guthke T, Bauer J, Sammler D, von Cramon DY: Neuropsychiatric findings in anti-Ma2-positive paraneoplastic limbic encephalitis. Neurology 2003; 61: 1159-1161
Figures and legends: Figure 1
Comparison of brain MRI scan images before (panel A and C) and after
radiation treatment (panel B and D). Panels A and B show sagittal T1 weighted images. Panels C and D show axial T1 weighted images at midbrain level. Panels A and C: MRI scan with gadolinium contrast prior to treatment show an enlarged, pineal gland with a similar area of enhancement in the suprasellar cistern involving the optic chiasm and mammillary bodies. The enhancement also extends to pituitary and corpus callosum. Figure 2
Western blotting analysis shows that serum of the patient contains
antibody directed to protein bands from normal human brain tissue. H indicates the position of the human immunoglobulin heavy chain; L indicates the immunoglobulin light chain. Molecular weight standard is marked on the left side of the panel. Total protein extracts of normal human tissues from brain, lung, heart, liver and kidney were separated by 12.5% SDS-PAGE and transferred to a nitrocellulose membrane. Serum was diluted at 1:100 and blotted with the membrane. A HRP conjugated goat anti-human IgG antibody was used as a secondary antibody at 1:3,000 dilution. ECL was performed to visualize the signal.
12
Figure 3
Indirect immunofluorescent staining shows that antibodies recognize
nuclear plasma proteins as well as particles associated with nucleoli. The staining was performed using Hep2 epithelial cells prefixed with methanol-acetone (Bion Enterprises Ltd., Park Ridge, IL, USA). Serum was diluted in PBS at ratios of 1:40, 1:80, 1: 160, and 1:320. The FITC conjugated goat anti-human IgG (Caltag Lab, Burlingame, CA, USA) diluted in PBS (1:200) was used as secondary detecting agent. The slide was mounted with Vecta-shield (Vector, Burlingame, CA, USA) and microscopic exam was performed. Magnification: approximately 250.
13
Fig 1
14
Fig 2
15
Fig 3
16
Presence of Anti-brain Antibodies in ObsessiveCompulsive Disorder Secondary to Pineal Gland Germinoma: a Case Report Weiguo Zhu M.D., Ph.D., Karl S. Burgoyne M. D., Ira M. Lesser M.D.
PII: DOI: Reference:
S0033-3182(14)00075-9 http://dx.doi.org/10.1016/j.psym.2014.05.001 PSYM458
To appear in:
Psychosomatics
Cite this article as: Weiguo Zhu M.D., Ph.D., Karl S. Burgoyne M.D., Ira M. Lesser M.D., Presence of Anti-brain Antibodies in Obsessive-Compulsive Disorder Secondary to Pineal Gland Germinoma: a Case Report, Psychosomatics, http://dx. doi.org/10.1016/j.psym.2014.05.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Presence of Anti-brain Antibodies in Obsessive-Compulsive
Disorder Secondary to Pineal Gland Germinoma: a Case Report Authors: Weiguo Zhu, M.D., Ph.D. Karl S Burgoyne, M.D. Ira M Lesser, M.D. Affiliation: Department of Psychiatry Harbor-UCLA Medical Center David-Geffen School of Medicine University of California, Los Angeles, Key words: obsessive-compulsive disorder; brain; tumor; autoantibodies; pineal gland Corresponding author: Dr. Weiguo Zhu Department of Psychiatry Harbor-UCLA Medical Center 1000 W Carson Street Torrance, CA 90509 Tel: 310-222-3103 Fax: 310-222-1815 E-mail: [email protected]
1
Abstract: Symptoms of obsessive-compulsive disorder (OCD) have been found to be associated with brain neoplasms. We report a case of OCD secondary to a brain pineal gland germinoma. The patient is a 23-year-old male with no past history of medical and psychiatric disorders. He had an onset of OCD symptoms after achieving radiological remission of the brain tumor. A serum sample from the patient was tested positive for the presence of anti-brain antibodies. Brain specific proteins of 43 kd and 45 kd were identified as target antigens using western blotting analysis.
Indirect immunofluorescent staining showed nuclear plasma as well as
nucleolar staining patterns. We present this case which may illustrate the autoimmune aspects of pathophysiology in OCD symptoms secondary to brain tumor.
Introduction: Obsessive-compulsive disorder (OCD) is a neuropsychiatric illness characterized by the experience of recurrent, intrusive, and distressing thoughts, images, and urges to action (1). It was considered a rare disorder, but new data have revealed that it is, in fact, a relatively common illness, particularly in childhood and adolescence (2). and pathophysiology of OCD are not well understood.
The etiology
Various factors involving
psychosocial, genetic, neuroanatomic, and neurochemical factors have been identified (36). A subset of patients with pediatric onset OCD and tic syndrome (e.g. Tourette's syndrome) have a symptom onset or exacerbation associated with group A betahemolytic streptococcal (GABHS) infection (7-10). The term “pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections” (PANDAS) has been coined to describe those patients with evidence of recent group A beta hemolytic streptococcal infection. Numerous studies have reported the presence of anti-brain, anti-
2
neuron, and anti-basal ganglia antibodies in these patients (11-14).
Pavone et al.
reported a study showing that 64% of patients with PANDAS are positive for anti-basal ganglia antibodies, but only 9% were positive compared to the group with GABHS infection without PANDAS (15).
Swedo proposed an autoimmune model where
antibodies against GABHS have cross-reactions with specific brain antigens and result in movement disorder and OCD symptoms (16). The target antigens remain unknown; however, a number of studies have reported identification of some neuronal proteins at 40 kd, 60 kd, and 83 kd as common target proteins (15, 17-19). Limbic encephalitis is an inflammation of the limbic system, which includes the thalamus, hypothalamus, hippocampus and amygadala. It has been reported as paraneoplastic syndrome associated with malignancies in lung, ovary, breast, etc. (20). Antibodies targeting the oncoproteins have cross reactions with cellular components in brain resulting in neurological symptoms. A series of antigens have been identifies, such as Hu, Ma, Ri, voltage gated potassium channel etc. (21). More recently, Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been characterized (22). It has predominant psychiatric symptoms during early phase of the illness, such as delusions and hallucinations, and often leads patients to seek psychiatric evaluation and treatment. The presence of autoantibodies against NMDAR, particularly NR1 subunit, in both serum and cerebral spinal fluid of patients has led to the hypothsis of an autoimmune mediated NMDA dysfunction where autoantibodies alter the structure and function of the receptor. Effective treatment with immune modulators further supports the hypothesis of autoimmune mechanism of the disease.
3
There are a number of cases reporting the onset of OCD symptoms secondary to brain tumors (23-27). In other cases, the OCD symptoms occurred after the surgical removal of the tumor or after successful treatment with radiation and chemotherapy (2831). We report a patient who developed OCD symptoms after the successful treatment of a pineal gland germinoma with radiation. We demonstrate the presence of anti-brain antibodies in the serum of this patient, and discuss the possibility of a tumor-induced immune attack of brain tissue in the pathogenesis of OCD.
Case report: Mr. B is a 23-year-old, right-handed male, previously in good physical and mental health. Over a period of 3 months, he developed headaches, bi-temporal vision loss, generalized weakness and memory loss. On physical examination, he had a right IVth nerve palsy and signs suggestive of mid-brain pathology. A brain magnetic resonance image (MRI) scan demonstrated an enlarged pineal gland with a similar area of enhancement in the suprasellar cistern involving the optic chiasm and mammilliary body, and evidence of pituitary extension (Fig. 1). There was no involvement in nuclei of the basal ganglia or other brain regions. The diagnosis of germinoma was confirmed by biopsy. Mr. B was successfully treated with a course of cranial irradiation, and he began a regimen of pituitary hormone replacement therapy which included: Prednisone 5 mg, and Levothyroxine 75 μg daily, Desmopressin 10 μg twice a day, and Testosterone injection 400 mg every 4 weeks.
Approximately three months after achieving
radiological remission, he developed a preoccupation with germs and fears of contracting bacteria, which prompted him to begin washing his hand extensively. His symptoms of OCD included obsessions about his homework assignment and contaminations with
4
germs, performing certain senseless tasks over and over again, such as checking and making sure he takes medications, checking his homework, etc. On the YBOCS (YaleBrown Obsessive-Compulsive Scale) (32, 33), he scored 29 on a 0 to 40 scale indicates moderate severity of symptoms. He denied experiencing any OCD symptoms or other psychiatric symptoms prior to the onset of brain tumor. He has a negative family history of psychiatric illness.
Results: Prior to the psychiatric treatment, 10 ml of whole blood was obtained from the patient. Serum of the patient was used for the following analyses. Figure 2 shows the western blotting analysis using the patient’s serum as the primary antibody. Total proteins from a number of normal human tissues were separated by SDS-PAGE and transferred on to a nitrocellulose membrane. A pair of protein bands of approximately 43 kd and 45 kd were observed in normal human brain tissue. These proteins appear brain specific, since no positive bands at the similar molecular weight range were found in other normal human tissues: lung, heart, liver, and kidney. In addition, serum from a normal human subject was used as a negative control generated no signal (data not shown). There are strong reactions with the proteins at both 25 kd and 50 kd in all tissues tested, which are presumably the human immunoglobulin heavy and light chains. The anti-brain antibodies are IgG class, because the secondary antibody used as a detection agent is IgG specific. The immune reactivity can be detected at a dilution of 1:100. Thus, the patient serum contains antibodies specific to proteins extracted from normal human brain tissue.
5
In order to understand the subcellular localizations of the antigens, we also performed indirect immunofluorescent staining similar to ANA staining. The patient serum generates a positive staining with Hep2 epithelial cells. Figure 3 shows a staining pattern of fine nuclear plasma staining as well as nucleolar staining, suggesting that the antibodies may recognize components in the ribonuclear complex. The staining pattern of mitotic cells indicates no DNA binding activities. The signal can be detected with up to 1:320 dilution of the serum.
Discussion: Various neurological disorders are accompanied with symptoms of OCD, e.g. encephalitis, drugs, head trauma, brain tumors, and PANDAS. There are at least eight case reports documenting the association of OCD symptoms with either the progression of brain tumor or remission after surgical removal of tumor or radiation treatment (2331). Ward first reported three cases of transient feelings of compulsion caused by hemispheric lesions (23).
All three patients experienced episodic, short lasting
neuropsychiatric symptoms and neurological deficits.
Brain lesions in frontal lobe,
temporal lobe, basal ganglia and cerebellum were subsequently identified.
The
neuropsychiatric symptoms may represent partial seizures since all three cases showed epileptic activities in EEG studies. Interestingly, there are four cases reporting that OCD symptoms started after surgical removal of brain tumor or successful radiation treatment of brain tumors. Craven (31) presented a case of a 15 year-old female who developed acute psychosis and OCD symptoms fourteen months after successful treatment of a pineal germinoma.
Mordecai et al. reported that a 13 year-old female who had a
supresellar germinoma with basal ganglia involvement presented with OCD and
6
psychotic symptoms (26). Our patient shares many common clinical and radiological features with both of these cases, although he was not psychotic. Intriguingly, these patients had no experience of psychiatric symptoms either prior to the onset of brain tumor, or shortly after the treatment. In all cases, there was a symptom-free period followed by OCD symptoms without evidence of tumor relapse when the OCD symptoms developed. This suggests that there is a delayed effect resulting from either tumor or from the surgical or radiation treatment in the regions, such as basal ganglia, anterior cingulate and orbital-frontal cortex. An alternative explanation for developing OCD symptoms in this patient is the presence of anti-brain specific antibodies in patient serum. We hypothesize that the destruction of brain tumor during surgery and radiation allowed the debris to be released into the circulation where the immune system recognized either neoplastic components or normal brain proteins that are normally sequestered from the immune system. The activation of the immune system would result in autoantibody production and/or cytotoxic cellular attack of brain tissue, which then could cause brain dysfunction. The possibility of a tumor-induced immune attack on brain structures, analogous to the paraneoplastic neurologic syndrome (34-36), has not previously been entertained. Scheid et al. reported a case in which the OCD symptoms were the first signs in a patient having testicular cancer and anti-Ma2 positive paraneoplastic limbic encephalitis (37). Ma2 is a neuronal protein of 40 kd and anti-Ma2 antibody is thought to be induced by the testicular cancer and be involved in paraneoplastic encephalitis and neuropsychiatric symptoms.
On indirect immunofluorescent staining, anti-Ma2 generates a nucleolar
staining pattern, similar to what we found in this patient.
7
Anti-brain antibodies have been identified in sera of patients with PANDAS. The 40 kd, 60 kd, 83 kd proteins are reported as target antigens. Hoekstra et al. has recently identified the 60 kd heat shock protein as a common antigen in tic disorders (19). We identified brain specific proteins of 43 kd and 45 kd as the targets of anti-brain antibodies. These proteins appear to be localized in nuclear plasma and nucleoli. The identities of these proteins remain to be determined. It is quite intriguing if these proteins could be part of the NMDAR. Base on the cases so far reported, NR1 subunit of NMDAR is the most common target of autoantibodies in anti-NMDA encephalitis. The molecular weight of NR1 is approximately 115 kd. Therefore, it is unlikely that our patient serum contains antibody against NR1. In addition, the immunofluorescent staining pattern suggested an intracellular localization of the antigens in question. Future studies will be carried out to delineate the molecular identities of these proteins and the localization of these proteins in brain. Characterization of the biological functions of these proteins might provide insight into the pathophysiology of OCD.
Acknowledgments: We are grateful to Dr. C. Mark Mehringer, Department of Radiology, HarborUCLA Medical Center for assistance with radiology evaluation of the patient. We thank Dr. Samuel French, Department of Pathology, Harbor-UCLA Medical Center for laboratory technical support. We also thank Drs. Edmond Pi, Andrew Ho, and Robert Berthold for their helpful discussion and critical review of the manuscript.
Financial Disclosures: The authors reports no financial relationships with commercial interests.
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Figures and legends: Figure 1
Comparison of brain MRI scan images before (panel A and C) and after
radiation treatment (panel B and D). Panels A and B show sagittal T1 weighted images. Panels C and D show axial T1 weighted images at midbrain level. Panels A and C: MRI scan with gadolinium contrast prior to treatment show an enlarged, pineal gland with a similar area of enhancement in the suprasellar cistern involving the optic chiasm and mammillary bodies. The enhancement also extends to pituitary and corpus callosum. Figure 2
Western blotting analysis shows that serum of the patient contains
antibody directed to protein bands from normal human brain tissue. H indicates the position of the human immunoglobulin heavy chain; L indicates the immunoglobulin light chain. Molecular weight standard is marked on the left side of the panel. Total protein extracts of normal human tissues from brain, lung, heart, liver and kidney were separated by 12.5% SDS-PAGE and transferred to a nitrocellulose membrane. Serum was diluted at 1:100 and blotted with the membrane. A HRP conjugated goat anti-human IgG antibody was used as a secondary antibody at 1:3,000 dilution. ECL was performed to visualize the signal.
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Figure 3
Indirect immunofluorescent staining shows that antibodies recognize
nuclear plasma proteins as well as particles associated with nucleoli. The staining was performed using Hep2 epithelial cells prefixed with methanol-acetone (Bion Enterprises Ltd., Park Ridge, IL, USA). Serum was diluted in PBS at ratios of 1:40, 1:80, 1: 160, and 1:320. The FITC conjugated goat anti-human IgG (Caltag Lab, Burlingame, CA, USA) diluted in PBS (1:200) was used as secondary detecting agent. The slide was mounted with Vecta-shield (Vector, Burlingame, CA, USA) and microscopic exam was performed. Magnification: approximately 250.
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Fig 1
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Fig 2
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Fig 3
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