Psychosomatics 2014:]:]]]–]]]
& 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Case Reports Autoimmune-Mediated Cognitive Impairment: A Case Report Bhargavi Devineni, M.B.B.S., Arun Venkatesan, M.D., Ph.D., Brian S. Appleby, M.D., Vani Rao, M.D.
Background Autoimmune encephalopathy encompasses a complex group of diseases with diverse clinical manifestations and therapeutic outcomes.1 Central nervous system (CNS) autoimmune inflammation can be triggered in multiple ways, including (1) systemic infections/vaccinations, (2) various cancers (paraneoplastic autoimmune encephalitis), (3) systemic autoimmune disorders, and (4) without an identifiable cause (e.g., nonparaneoplastic autoimmune encephalitis).2 The discovery of neuropsychiatric disorders associated with antibodies to neuronal cell surface proteins, which play a crucial role in synaptic transmission and plasticity, has resulted in a paradigm shift in our understanding of CNS autoimmunity.3 We report a case of a young woman with multiple autoimmune disorders who presented with significant memory problems and relapse of major depressive disorder. Her cognitive problems did not resolve upon treatment of depression and continued to result in significant impairment of her daily functioning. A comprehensive neuropsychiatric and neurologic evaluation helped in establishing and providing a successful treatment. This case underscores the importance of recognizing neuropsychiatric manifestations of autoimmune disorders and the use of a multidisciplinary approach for the evaluation and treatment of neuropsychiatric conditions.
Case Report Ms. A, a 31-year-old engineer, presented to our psychiatric clinic with 1-year insidious course of Psychosomatics ]:], ] 2014
waxing and waning cognitive difficulties. She reported forgetting tasks, conversations, and names as well as feeling easily overwhelmed by previously simple cognitive activities. As an example, she described having difficulty in understanding the term “2-hour delay” despite several explanations by multiple people. She reported bradyphrenia, intermittent episodes of vertigo, impaired balance, increased clumsiness, and she often dropped things. Her cognitive deficits fluctuated over time, without gradual progression. Her performance at work and home declined during periods of worsening. She had difficulty recalling conversations she had with her husband and coworkers, parts of different machines at work, and the people responsible for these parts. She also reported forgetting to pay bills and that she was unable to do her job without taking notes, needing to write down explicit instructions, and having difficulty with simple mathematics. For example, while she was tutoring a school student and was attempting a basic division problem, she could not figure out where she should place the decimal point.
Received August 29, 2013; revised December 26, 2013; accepted December 27, 2013. From Division of Geriatrics and Neuropsychiatry, Department of Psychiatry, Johns Hopkins University of Medicine, Baltimore, MD; Division of Neuroimmunology and Neuroinfectious diseases, Department of Neurology, Johns Hopkins University of Medicine, Baltimore, MD ; Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH. Send correspondence and reprint requests to Bhargavi Devineni, M.B.B.S., Division of Geriatrics and Neuropsychiatry, Department of Psychiatry, Johns Hopkins University of Medicine, 5300 Alpha Commons Drive 4th Floor, Alpha Commons Building, Baltimore, MD 21224; e-mail: [email protected] & 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
www.psychosomaticsjournal.org
1
Case Reports She had previously experienced an episode of major depression that responded well to treatment. She was in remission, not having taken antidepressants for 2 years before the onset of cognitive difficulties. She experienced a relapse of major depression symptoms 2 months after the onset of cognitive problems. Administration of 75 mg/d of extended release venlafaxine led to improvement in depressive symptoms, but her cognitive problems persisted. Even though she scored 100 of 100 on the Modified Mini-Mental State Examination, comprehensive neuropsychologic testing revealed deficits in verbal and visual delayed memory, processing speed, and simple visual reaction time.
Pertinent Medical History Before Onset of Cognitive Impairment Ms. A developed autoimmune Type 1 diabetes mellitus (DM) about 9 years, and Graves disease about 4 years, before the onset of cognitive impairment. She underwent radioactive iodine treatment for Graves disease and continued thyroid hormone replacement for hypothyroidism. Shortly after the onset of Graves disease, Graves ophthalmopathy developed coinciding with an episode of major depression. She responded well to treatment with sertraline and her depression remitted. However, diabetes mellitus was not well controlled despite treatment with insulin pump. About 2 years before onset of cognitive problems, Ms. A also developed hypertension that responded well to lisinopril. Given her young age, fluctuating cognitive course, and history of systemic autoimmune disease, we considered a diagnosis of autoimmune encephalopathy and
TABLE.
2
referred her to a neurologist for further workup and treatment. Neuropsychiatric Workup and Positive Diagnostic Findings On neurologic examination, Ms. A’s scores were 29 of 30 on the Mini-Mental State Examination, her forward digit span was 7, and her reverse digit span was 4. She displayed no deficits in her cranial nerves, motor or sensory function, deep tendon reflexes, coordination, or gait. The findings of brain magnetic resonance imaging were normal. The results of a complete metabolic profile were normal, except for an elevated blood glucose (140 mg/dL). A complete blood count and vitamin B12, folate, and methylmalonic acid levels were normal. She had low thyroid stimulating hormone levels (0.13 uIU/mL; normal range: 0.50–4.50) and elevated hemoglobin A1C levels (6.8%; normal range: 4.5–6.1). The findings of cerebrospinal fluid (CSF) studies, including cell counts, protein, glucose, venereal disease research laboratory test, oligoclonal bands, and IgG index, were unremarkable. An autoimmune workup was significant for an elevated thyroid stimulating globulin (TSI) and anti-glutamic acid decarboxylase-65 (anti-GAD65) antibodies (Table 1). Treatment response Ms. A received 4 days of intravenous immunoglobulin (IVIG) infusion 30 months after the onset of cognitive symptoms. Within 2 months, she reported marked improvement in her cognitive symptoms and work
Pertinent Autoimmune Diagnostic Workup
Test
Result
Normal
Thyroid stimulating immunoglobulin (TSI) Erythrocyte sedimentation rate Rheumatoid factor Anti-nuclear antibody titer (ANA) Thyroglobulin antibody Thyroid peroxidase antibody C-reactive protein
526% (high) 16 mm/h o 20 IU/mL 80 (speckled pattern) 7 WHO units 0 WHO units 0.2 mg/dL
o 140% 4–25 o 36 IU/mL; negative
Serum anti-glutamic acid decarboxylase (GAD)-65 (anti-GAD65) antibody assay Serum immunoglobulin G (IGG) Serum albumin Serum myelin basic protein Mayo paraneoplastic autoantibody panel-2
4 2.03 nmol/L (high) 966 mg/dL 4280 mg/dL Negative Negative
r 0.02 nmol/L 751–1560 3600–5100
www.psychosomaticsjournal.org
0–100; negative 0–100; negative 0–0.5
Psychosomatics ]:], ] 2014
Devineni et al. performance. She was able to remember conversations and instructions without having to take notes. Her MiniMental State Examination scores were 30 of 30, and her forward digit span had improved to 8 and reverse digit span to 6. She had a very good and sustained improvement in her cognitive symptoms, even a year after the treatment. Ms. A felt that she was back to her cognitive baseline and did not wish to pursue neuropsychologic assessment. In addition, her insulin use decreased. In particular, following treatment, the average basal rate of insulin used was 0.95 U/h compared with 1.8 U/h before treatment with IVIG. She also showed an improvement in the symptoms of Graves ophthalmopathy. She has not required maintenance treatment with IVIG.
Discussion Autoimmune encephalopathy encompasses a complex group of diseases with diverse immunologic associations, clinical manifestations, and therapeutic outcomes.1 In the last 50 years, there have been discoveries of several neuronal autoantibodies and clinical reports identifying patients with these autoantibodies.4,5 These findings support the concept of a broader spectrum of autoimmune cognitive impairment than “limbic encephalitis.”5 Neuronal Autoantibodies Neuronal autoantibodies have been divided into 3 classes based on the cell proteins or CNS antigens they target.3 These include the following: (1) Antibodies against nuclear or intracellular proteins: These antibodies are often associated with cancer. For example, antibodies against Hu are often associated with small cell lung cancer, anti-Ma2 antibodies with testicular germ cell tumors or non– small cell lung cancers, anti–collapsin response mediator proteins antibodies with small cell lung cancer or thymoma, and anti-Ri antibodies with carcinoid tumors.3,6 These antigens are not directly pathogenic but are considered markers of an immune response predominantly mediated by T cells. Neurologic disorders associated with these autoantibodies respond poorly to treatment.3 (2) Antibodies against intracellular synaptic proteins: These include GAD65 and amphysin. Autoantibodies Psychosomatics ]:], ] 2014
against these proteins may mediate disruption of synaptic vesicular fusion and reuptake of the neurotransmitters by both T cell-mediated immune response and direct antibody-mediated damage.3 (3) Antibodies against cell surface proteins: Recognition of cell surface synaptic proteins (i.e., N-methylD-aspartate acid receptor, α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor, γ-amino butyric acid B receptor, leucine rich glioma inactivated protein, voltage-gated potassium channel, Caspr2, GlyR, and mGluR5) by antibodies results in disrupted synaptic signaling.3 The latter 2 types of antigens are less commonly associated with malignancy. The prognosis of autoimmune encephalopathy related to antibodies against cell surface proteins is significantly better (with treatment) than that associated with nuclear or intracellular proteins.3 Clinical Manifestation CNS inflammatory disorders (e.g., autoimmune encephalopathies and dementias) lie on a spectrum that includes classic limbic encephalitis (subacute onset, memory loss, altered sensorium, seizures, personality, and mood change) disorders with atypical presentations and no altered sensorium, and those that may mimic rapidly progressive neurodegenerative disorders.7 Autoimmune encephalopathy is more common in women, and nonparaneoplastic autoimmune cognitive impairment is seen more frequently during midlife and or elderly populations. Other clinical features supporting the diagnosis of autoimmune cognitive impairment are subacute onset of cognitive impairment with either a rapidly progressive or fluctuating course. Memory loss, to a variable degree, and neurologic symptoms such as tremor and myoclonus are frequently reported. A personal or family history of autoimmunity further increases suspicion for autoimmune encephalopathy.5 Hashimoto encephalopathy, also known as encephalopathy associated with autoimmune thyroid disease and steroid-responsive encephalopathy with autoimmune thyroiditis, is a condition that presents with a variety of neuropsychiatric symptoms and signs with a presumed autoimmune etiology.8,9 These conditions are reported in patients with clinical or subclinical autoimmune thyroid disease such as Hashimoto thyroiditis and Graves disease.8 Its diagnosis is one of www.psychosomaticsjournal.org
3
Case Reports exclusion of other identifiable causes of encephalopathy and is characterized by neurologic and psychiatric symptoms, high levels of antithyroid antibodies in the serum or CSF or both, increased CSF protein concentration, nonspecific diffuse electroencephalogram abnormalities, and responsiveness to corticosteroid treatment. Antithyroperoxidase and antithyroglobulin antibodies are often present in the CSF of patients with steroid-responsive encephalopathy with autoimmune thyroiditis; however; their role in pathogenesis is not defined.8 Cognitive impairment often accompanies acute Graves disease but usually resolves in about a year following treatment.10 A 65-kDa enzyme-glutamic acid decarboxylase (GAD 65) catalyzes the conversion of glutamic acid to γ-amino butyric acid, a major inhibitory neurotransmitter of the CNS. The classic syndrome associated with elevated anti-GAD65 antibodies is stiff person syndrome. It often presents with muscular rigidity and trigger-induced painful spasms affecting the thoracolumbar paraspinal or abdominal muscles, which may gradually spread to the proximal limb muscles, leading to ataxia with an insidious onset.11 Anti-GAD65 antibodies are observed in 80% of patients with autoimmune type 1 DM. They come as 2 isoforms of GAD: 65 and 67 kDa and are found in pancreatic beta cells as well as γ-amino butyric acid neurons.12 A recent study reported the association of high levels of anti-GAD antibodies in patients with type 1 DM who presented with a spectrum of neurologic disorders including cerebellar degeneration, limbic encephalitis, and stiff person syndrome. The authors of this study concluded that demonstration of increased intrathecal synthesis of GAD antibody was important to confirm the association of GAD autoimmunity with neurologic syndrome with coexistence of type 1 DM.13 Anti-GAD65 antibody titers are typically reported as IU/mL (upper limit of normal 5) or nmol/L (upper limit of normal 0.02 nmol/L). A wide range of GAD65 antibody titers are associated with nonparaneoplastic syndromes. Mata et al. described 2 cases of intractable temporal lobe epilepsy with elevated titers of anti-GAD antibodies in both the serum and the CSF. Both patients responded to immunotherapy. These 2 patients did not have type 1 DM and the titers of anti-GAD antibodies were lower than 100 UI/mL.14 However, a study of patients with type 1 DM reported a spectrum of neurologic 4
www.psychosomaticsjournal.org
syndromes including limbic encephalitis with high anti-GAD titers defined as greater than 2000 U/mL.13 Ms. A’s young age, persistent cognitive problems despite improvement in symptoms of depression, subacute and fluctuating course of cognitive symptoms, and coexistence of 2 autoimmune illnesses prompted us to pursue investigation for a CNS autoimmune etiology. Our workup revealed elevated levels of antibodies (thyroid stimulating immune globulin and anti-GAD65 antibodies). Ms. A had high titers of serum anti-GAD65 antibody assay (4 2.03 nmol/L) but did not have symptoms of stiff person syndrome. She also did not have a presentation that is typical for limbic encephalitis. It is important to note that CSF anti-GAD65 antibody titers were not obtained for Ms. A and thus prevents us from demonstrating intrathecal synthesis of GAD antibody. However, the detection of the high titers of serum anti-GAD65 in Ms. A increases the likelihood of an autoimmune etiology for her cognitive impairment, as was corroborated by a very good response to immunotherapy. We do not imply that every patient who presents with cognitive impairment requires a workup for autoimmune encephalopathy. The initial step in the evaluation of cognitive impairment is to exclude treatable causes (i.e., infectious, therapeutic, metabolic, nutritional, psychiatric, neoplastic, toxic, or vascular). Atypical neuroimaging findings (such as mild leukoaraiosis, mild to moderate generalized atrophic changes, and diffuse or asymmetric hypoperfusion), neural antibodies, or inflammatory markers within the CSF are possible indicators of autoimmune cognitive impairment.5 We recommend that one should consider an autoimmune etiology for cognitive impairment based on the clinical presentation and individual patient risk factors. Presence of an autoimmune illness could increase the likelihood of other organ autoimmunity and thus CNS autoimmunity.15 Treatment Patients with nonparaneoplastic autoimmune encephalopathy can respond well to immunotherapy. However, information about treatment for autoimmune cognitive impairment is mostly limited to retrospective case series or expert opinion.16 There is no definitive evidence-based medicine support for immunotherapy. A recent study reviewed the clinical course and predictors of immunotherapy in 75 patients with autoimmune encephalopathy. The authors report subacute onset, fluctuating Psychosomatics ]:], ] 2014
Devineni et al. course, and pure cognitive presentation as predictors of good response to immunotherapy.5 Usually, an initial high dose of intravenous steroids is given over the course of several days (e.g., 1 g of methylprednisolone intravenously for 5 days) as an empirical treatment trial. This was not chosen for Ms. A because of type 1 DM and labile blood glucose levels. Rather, IVIG was chosen as an empiric therapy, given its effectiveness in some cases of autoimmune encephalopathy.17 With immunotherapy, Ms. A not only showed improvement in cognitive symptoms, but her insulin requirement was also reduced. Nevertheless, it is important to note that there is no confirmatory evidence that IVIG alters insulin requirement in patients with type 1 DM nor are we recommending this treatment for patients with type 1 DM.
urgent need to develop additional biomarkers and evidence-based treatments for these disorders. The presence of systemic autoimmune disease, subacute onset of cognitive dysfunctions, and favorable response to immunotherapy in Ms. A supports the diagnosis of autoimmune-mediated cognitive dysfunction and underscores the importance of considering autoimmune causes in the differential diagnosis of cognitive dysfunction. However, our understanding of the immunologic pathogenesis of neuropsychiatric syndromes is still evolving, and given that CNS autoimmune disorders can present with psychiatric manifestations, it is important to do a comprehensive diagnostic workup and collaborate with other specialists before concluding and restricting treatment to primary psychiatric syndromes.
Conclusion In summary, the present case highlights the heterogeneity of autoimmune encephalopathies and the
Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.
References 1. Flanagan E, Caselli R: Autoimmune encephalopathy. Semin Neurol 2011; 31:144–157 2. Melzer N, Meuth SG, Wiendl H: Paraneoplastic and nonparaneoplastic autoimmunity to neurons in the central nervous system. J Neurol 2013; 260:1215–1233 3. Lancaster E, Dalmau J: Neuronal autoantigens—pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 2012; 8:380–390 4. Tuzun E, Dalmau J: Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist 2007; 13:261–271 5. Flanagan EP, McKeon A, Lennon VA, et al: Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc 2010; 85:881–897 6. Foster AR, Caplan JP: Paraneoplastic limbic encephalitis. Psychosomatics 2009; 50:108–113 7. McKeon A: Immunotherapeutics for autoimmune encephalopathies and dementias. Curr Treat Options Neurol 2013; 15(6):723–737 8. Tamagno G, Celik Y, Simó R, et al: Encephalopathy associated with autoimmune thyroid disease in patients with Graves’ disease: clinical manifestations, follow-up, and outcomes. BMC Neurol 2010; 10:27 9. Lee SW, Donlon S, Caplan JP: Steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) or Hashimoto’s encephalopathy: a case and review. Psychosomatics 2011; 52:99–108
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10. Vogel A, Elberling TV, Hørding M, et al: Affective symptoms and cognitive functions in the acute phase of Graves’ thyrotoxicosis. Psychoneuroendocrinology 2007; 32:36–43 11. Ciccoto G, Blaya M, Kelley RE: Stiff person syndrome. Neurol Clin 2013; 31:319–328 12. Lopez-Sublet M, Bihan H, Reach G, et al: Limbic encephalitis and type 1 diabetes with glutamic acid decarboxylase 65 (GAD65) autoimmunity: Improvement with high-dose intravenous immunoglobulin therapy. Diabetes Metab 2012; 38:273–275 13. Saiz A, Blanco Y, Sabater L, et al: Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 2008; 131:2553–2563 14. Matà S, Muscas GC, Naldi I, et al: Non-paraneoplastic limbic encephalitis associated with anti-glutamic acid decarboxylase antibodies. J. Neuroimmunol 2008; 199:155–159 15. Van den Driessche A, Eenkhoorn V, Van Gaal L, et al: Type 1 diabetes and autoimmune polyglandular syndrome: a clinical review. Neth J Med 2009; 2013:376–387 16. McKeon A, Lennon VA, Pittock SJ: Immunotherapyresponsive dementias and encephalopathies. Lifelong Learning in Neurology, 16. CONTINUUM; 2010; 80–101 2010 17. Titulaer MJ, McCracken L, Gabilondo I, et al: Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12:157–165
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& 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Case Reports Autoimmune-Mediated Cognitive Impairment: A Case Report Bhargavi Devineni, M.B.B.S., Arun Venkatesan, M.D., Ph.D., Brian S. Appleby, M.D., Vani Rao, M.D.
Background Autoimmune encephalopathy encompasses a complex group of diseases with diverse clinical manifestations and therapeutic outcomes.1 Central nervous system (CNS) autoimmune inflammation can be triggered in multiple ways, including (1) systemic infections/vaccinations, (2) various cancers (paraneoplastic autoimmune encephalitis), (3) systemic autoimmune disorders, and (4) without an identifiable cause (e.g., nonparaneoplastic autoimmune encephalitis).2 The discovery of neuropsychiatric disorders associated with antibodies to neuronal cell surface proteins, which play a crucial role in synaptic transmission and plasticity, has resulted in a paradigm shift in our understanding of CNS autoimmunity.3 We report a case of a young woman with multiple autoimmune disorders who presented with significant memory problems and relapse of major depressive disorder. Her cognitive problems did not resolve upon treatment of depression and continued to result in significant impairment of her daily functioning. A comprehensive neuropsychiatric and neurologic evaluation helped in establishing and providing a successful treatment. This case underscores the importance of recognizing neuropsychiatric manifestations of autoimmune disorders and the use of a multidisciplinary approach for the evaluation and treatment of neuropsychiatric conditions.
Case Report Ms. A, a 31-year-old engineer, presented to our psychiatric clinic with 1-year insidious course of Psychosomatics ]:], ] 2014
waxing and waning cognitive difficulties. She reported forgetting tasks, conversations, and names as well as feeling easily overwhelmed by previously simple cognitive activities. As an example, she described having difficulty in understanding the term “2-hour delay” despite several explanations by multiple people. She reported bradyphrenia, intermittent episodes of vertigo, impaired balance, increased clumsiness, and she often dropped things. Her cognitive deficits fluctuated over time, without gradual progression. Her performance at work and home declined during periods of worsening. She had difficulty recalling conversations she had with her husband and coworkers, parts of different machines at work, and the people responsible for these parts. She also reported forgetting to pay bills and that she was unable to do her job without taking notes, needing to write down explicit instructions, and having difficulty with simple mathematics. For example, while she was tutoring a school student and was attempting a basic division problem, she could not figure out where she should place the decimal point.
Received August 29, 2013; revised December 26, 2013; accepted December 27, 2013. From Division of Geriatrics and Neuropsychiatry, Department of Psychiatry, Johns Hopkins University of Medicine, Baltimore, MD; Division of Neuroimmunology and Neuroinfectious diseases, Department of Neurology, Johns Hopkins University of Medicine, Baltimore, MD ; Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH. Send correspondence and reprint requests to Bhargavi Devineni, M.B.B.S., Division of Geriatrics and Neuropsychiatry, Department of Psychiatry, Johns Hopkins University of Medicine, 5300 Alpha Commons Drive 4th Floor, Alpha Commons Building, Baltimore, MD 21224; e-mail: [email protected] & 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
www.psychosomaticsjournal.org
1
Case Reports She had previously experienced an episode of major depression that responded well to treatment. She was in remission, not having taken antidepressants for 2 years before the onset of cognitive difficulties. She experienced a relapse of major depression symptoms 2 months after the onset of cognitive problems. Administration of 75 mg/d of extended release venlafaxine led to improvement in depressive symptoms, but her cognitive problems persisted. Even though she scored 100 of 100 on the Modified Mini-Mental State Examination, comprehensive neuropsychologic testing revealed deficits in verbal and visual delayed memory, processing speed, and simple visual reaction time.
Pertinent Medical History Before Onset of Cognitive Impairment Ms. A developed autoimmune Type 1 diabetes mellitus (DM) about 9 years, and Graves disease about 4 years, before the onset of cognitive impairment. She underwent radioactive iodine treatment for Graves disease and continued thyroid hormone replacement for hypothyroidism. Shortly after the onset of Graves disease, Graves ophthalmopathy developed coinciding with an episode of major depression. She responded well to treatment with sertraline and her depression remitted. However, diabetes mellitus was not well controlled despite treatment with insulin pump. About 2 years before onset of cognitive problems, Ms. A also developed hypertension that responded well to lisinopril. Given her young age, fluctuating cognitive course, and history of systemic autoimmune disease, we considered a diagnosis of autoimmune encephalopathy and
TABLE.
2
referred her to a neurologist for further workup and treatment. Neuropsychiatric Workup and Positive Diagnostic Findings On neurologic examination, Ms. A’s scores were 29 of 30 on the Mini-Mental State Examination, her forward digit span was 7, and her reverse digit span was 4. She displayed no deficits in her cranial nerves, motor or sensory function, deep tendon reflexes, coordination, or gait. The findings of brain magnetic resonance imaging were normal. The results of a complete metabolic profile were normal, except for an elevated blood glucose (140 mg/dL). A complete blood count and vitamin B12, folate, and methylmalonic acid levels were normal. She had low thyroid stimulating hormone levels (0.13 uIU/mL; normal range: 0.50–4.50) and elevated hemoglobin A1C levels (6.8%; normal range: 4.5–6.1). The findings of cerebrospinal fluid (CSF) studies, including cell counts, protein, glucose, venereal disease research laboratory test, oligoclonal bands, and IgG index, were unremarkable. An autoimmune workup was significant for an elevated thyroid stimulating globulin (TSI) and anti-glutamic acid decarboxylase-65 (anti-GAD65) antibodies (Table 1). Treatment response Ms. A received 4 days of intravenous immunoglobulin (IVIG) infusion 30 months after the onset of cognitive symptoms. Within 2 months, she reported marked improvement in her cognitive symptoms and work
Pertinent Autoimmune Diagnostic Workup
Test
Result
Normal
Thyroid stimulating immunoglobulin (TSI) Erythrocyte sedimentation rate Rheumatoid factor Anti-nuclear antibody titer (ANA) Thyroglobulin antibody Thyroid peroxidase antibody C-reactive protein
526% (high) 16 mm/h o 20 IU/mL 80 (speckled pattern) 7 WHO units 0 WHO units 0.2 mg/dL
o 140% 4–25 o 36 IU/mL; negative
Serum anti-glutamic acid decarboxylase (GAD)-65 (anti-GAD65) antibody assay Serum immunoglobulin G (IGG) Serum albumin Serum myelin basic protein Mayo paraneoplastic autoantibody panel-2
4 2.03 nmol/L (high) 966 mg/dL 4280 mg/dL Negative Negative
r 0.02 nmol/L 751–1560 3600–5100
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0–100; negative 0–100; negative 0–0.5
Psychosomatics ]:], ] 2014
Devineni et al. performance. She was able to remember conversations and instructions without having to take notes. Her MiniMental State Examination scores were 30 of 30, and her forward digit span had improved to 8 and reverse digit span to 6. She had a very good and sustained improvement in her cognitive symptoms, even a year after the treatment. Ms. A felt that she was back to her cognitive baseline and did not wish to pursue neuropsychologic assessment. In addition, her insulin use decreased. In particular, following treatment, the average basal rate of insulin used was 0.95 U/h compared with 1.8 U/h before treatment with IVIG. She also showed an improvement in the symptoms of Graves ophthalmopathy. She has not required maintenance treatment with IVIG.
Discussion Autoimmune encephalopathy encompasses a complex group of diseases with diverse immunologic associations, clinical manifestations, and therapeutic outcomes.1 In the last 50 years, there have been discoveries of several neuronal autoantibodies and clinical reports identifying patients with these autoantibodies.4,5 These findings support the concept of a broader spectrum of autoimmune cognitive impairment than “limbic encephalitis.”5 Neuronal Autoantibodies Neuronal autoantibodies have been divided into 3 classes based on the cell proteins or CNS antigens they target.3 These include the following: (1) Antibodies against nuclear or intracellular proteins: These antibodies are often associated with cancer. For example, antibodies against Hu are often associated with small cell lung cancer, anti-Ma2 antibodies with testicular germ cell tumors or non– small cell lung cancers, anti–collapsin response mediator proteins antibodies with small cell lung cancer or thymoma, and anti-Ri antibodies with carcinoid tumors.3,6 These antigens are not directly pathogenic but are considered markers of an immune response predominantly mediated by T cells. Neurologic disorders associated with these autoantibodies respond poorly to treatment.3 (2) Antibodies against intracellular synaptic proteins: These include GAD65 and amphysin. Autoantibodies Psychosomatics ]:], ] 2014
against these proteins may mediate disruption of synaptic vesicular fusion and reuptake of the neurotransmitters by both T cell-mediated immune response and direct antibody-mediated damage.3 (3) Antibodies against cell surface proteins: Recognition of cell surface synaptic proteins (i.e., N-methylD-aspartate acid receptor, α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor, γ-amino butyric acid B receptor, leucine rich glioma inactivated protein, voltage-gated potassium channel, Caspr2, GlyR, and mGluR5) by antibodies results in disrupted synaptic signaling.3 The latter 2 types of antigens are less commonly associated with malignancy. The prognosis of autoimmune encephalopathy related to antibodies against cell surface proteins is significantly better (with treatment) than that associated with nuclear or intracellular proteins.3 Clinical Manifestation CNS inflammatory disorders (e.g., autoimmune encephalopathies and dementias) lie on a spectrum that includes classic limbic encephalitis (subacute onset, memory loss, altered sensorium, seizures, personality, and mood change) disorders with atypical presentations and no altered sensorium, and those that may mimic rapidly progressive neurodegenerative disorders.7 Autoimmune encephalopathy is more common in women, and nonparaneoplastic autoimmune cognitive impairment is seen more frequently during midlife and or elderly populations. Other clinical features supporting the diagnosis of autoimmune cognitive impairment are subacute onset of cognitive impairment with either a rapidly progressive or fluctuating course. Memory loss, to a variable degree, and neurologic symptoms such as tremor and myoclonus are frequently reported. A personal or family history of autoimmunity further increases suspicion for autoimmune encephalopathy.5 Hashimoto encephalopathy, also known as encephalopathy associated with autoimmune thyroid disease and steroid-responsive encephalopathy with autoimmune thyroiditis, is a condition that presents with a variety of neuropsychiatric symptoms and signs with a presumed autoimmune etiology.8,9 These conditions are reported in patients with clinical or subclinical autoimmune thyroid disease such as Hashimoto thyroiditis and Graves disease.8 Its diagnosis is one of www.psychosomaticsjournal.org
3
Case Reports exclusion of other identifiable causes of encephalopathy and is characterized by neurologic and psychiatric symptoms, high levels of antithyroid antibodies in the serum or CSF or both, increased CSF protein concentration, nonspecific diffuse electroencephalogram abnormalities, and responsiveness to corticosteroid treatment. Antithyroperoxidase and antithyroglobulin antibodies are often present in the CSF of patients with steroid-responsive encephalopathy with autoimmune thyroiditis; however; their role in pathogenesis is not defined.8 Cognitive impairment often accompanies acute Graves disease but usually resolves in about a year following treatment.10 A 65-kDa enzyme-glutamic acid decarboxylase (GAD 65) catalyzes the conversion of glutamic acid to γ-amino butyric acid, a major inhibitory neurotransmitter of the CNS. The classic syndrome associated with elevated anti-GAD65 antibodies is stiff person syndrome. It often presents with muscular rigidity and trigger-induced painful spasms affecting the thoracolumbar paraspinal or abdominal muscles, which may gradually spread to the proximal limb muscles, leading to ataxia with an insidious onset.11 Anti-GAD65 antibodies are observed in 80% of patients with autoimmune type 1 DM. They come as 2 isoforms of GAD: 65 and 67 kDa and are found in pancreatic beta cells as well as γ-amino butyric acid neurons.12 A recent study reported the association of high levels of anti-GAD antibodies in patients with type 1 DM who presented with a spectrum of neurologic disorders including cerebellar degeneration, limbic encephalitis, and stiff person syndrome. The authors of this study concluded that demonstration of increased intrathecal synthesis of GAD antibody was important to confirm the association of GAD autoimmunity with neurologic syndrome with coexistence of type 1 DM.13 Anti-GAD65 antibody titers are typically reported as IU/mL (upper limit of normal 5) or nmol/L (upper limit of normal 0.02 nmol/L). A wide range of GAD65 antibody titers are associated with nonparaneoplastic syndromes. Mata et al. described 2 cases of intractable temporal lobe epilepsy with elevated titers of anti-GAD antibodies in both the serum and the CSF. Both patients responded to immunotherapy. These 2 patients did not have type 1 DM and the titers of anti-GAD antibodies were lower than 100 UI/mL.14 However, a study of patients with type 1 DM reported a spectrum of neurologic 4
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syndromes including limbic encephalitis with high anti-GAD titers defined as greater than 2000 U/mL.13 Ms. A’s young age, persistent cognitive problems despite improvement in symptoms of depression, subacute and fluctuating course of cognitive symptoms, and coexistence of 2 autoimmune illnesses prompted us to pursue investigation for a CNS autoimmune etiology. Our workup revealed elevated levels of antibodies (thyroid stimulating immune globulin and anti-GAD65 antibodies). Ms. A had high titers of serum anti-GAD65 antibody assay (4 2.03 nmol/L) but did not have symptoms of stiff person syndrome. She also did not have a presentation that is typical for limbic encephalitis. It is important to note that CSF anti-GAD65 antibody titers were not obtained for Ms. A and thus prevents us from demonstrating intrathecal synthesis of GAD antibody. However, the detection of the high titers of serum anti-GAD65 in Ms. A increases the likelihood of an autoimmune etiology for her cognitive impairment, as was corroborated by a very good response to immunotherapy. We do not imply that every patient who presents with cognitive impairment requires a workup for autoimmune encephalopathy. The initial step in the evaluation of cognitive impairment is to exclude treatable causes (i.e., infectious, therapeutic, metabolic, nutritional, psychiatric, neoplastic, toxic, or vascular). Atypical neuroimaging findings (such as mild leukoaraiosis, mild to moderate generalized atrophic changes, and diffuse or asymmetric hypoperfusion), neural antibodies, or inflammatory markers within the CSF are possible indicators of autoimmune cognitive impairment.5 We recommend that one should consider an autoimmune etiology for cognitive impairment based on the clinical presentation and individual patient risk factors. Presence of an autoimmune illness could increase the likelihood of other organ autoimmunity and thus CNS autoimmunity.15 Treatment Patients with nonparaneoplastic autoimmune encephalopathy can respond well to immunotherapy. However, information about treatment for autoimmune cognitive impairment is mostly limited to retrospective case series or expert opinion.16 There is no definitive evidence-based medicine support for immunotherapy. A recent study reviewed the clinical course and predictors of immunotherapy in 75 patients with autoimmune encephalopathy. The authors report subacute onset, fluctuating Psychosomatics ]:], ] 2014
Devineni et al. course, and pure cognitive presentation as predictors of good response to immunotherapy.5 Usually, an initial high dose of intravenous steroids is given over the course of several days (e.g., 1 g of methylprednisolone intravenously for 5 days) as an empirical treatment trial. This was not chosen for Ms. A because of type 1 DM and labile blood glucose levels. Rather, IVIG was chosen as an empiric therapy, given its effectiveness in some cases of autoimmune encephalopathy.17 With immunotherapy, Ms. A not only showed improvement in cognitive symptoms, but her insulin requirement was also reduced. Nevertheless, it is important to note that there is no confirmatory evidence that IVIG alters insulin requirement in patients with type 1 DM nor are we recommending this treatment for patients with type 1 DM.
urgent need to develop additional biomarkers and evidence-based treatments for these disorders. The presence of systemic autoimmune disease, subacute onset of cognitive dysfunctions, and favorable response to immunotherapy in Ms. A supports the diagnosis of autoimmune-mediated cognitive dysfunction and underscores the importance of considering autoimmune causes in the differential diagnosis of cognitive dysfunction. However, our understanding of the immunologic pathogenesis of neuropsychiatric syndromes is still evolving, and given that CNS autoimmune disorders can present with psychiatric manifestations, it is important to do a comprehensive diagnostic workup and collaborate with other specialists before concluding and restricting treatment to primary psychiatric syndromes.
Conclusion In summary, the present case highlights the heterogeneity of autoimmune encephalopathies and the
Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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