Glutamic Acid Decarboxylase Autoimmunity With Brainstem, Extrapyramidal, and Spinal Cord Dysfunction

Pittock, Sean J.; Yoshikawa, Hiroaki; Ahlskog, J. Eric; Tisch, Stephen; Benarroch, Eduardo E.; Kryzer, Thomas J.; Lennon, Vanda A.

doi:10.4065/81.9.1207

Cited by 209 publications

(178 citation statements)

References 38 publications

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“…Case series of patients with autoimmune CNS disorders has demonstrated that early immunotherapy confers a better treatment outcome than delayed therapy. 45,59,60 The immunotherapy protocol may be subdivided into acute therapy and chronic therapy. Before starting immunotherapy, baseline evaluations should be performed to establish clinical parameters for objective monitoring of treatment response.…”

Section: Immunotherapymentioning

confidence: 99%

Paraneoplastic and Other Autoimmune Disorders of the Central Nervous System

McKeon

2013

The Neurohospitalist

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As a result of the burgeoning growth of disease-specific neural autoantibody markers available for diagnostic patient evaluation, there has been increasing awareness of autoimmune central nervous system (CNS) disorders in hospital practice. Hospital-based neurologists have also taken great interest in these disorders since many occur in the setting of an occult systemic cancer which can be detected and treated at an early stage, and many affected patients are responsive to immunotherapy. Associated neurological disorders are typically subacute in onset, some are common or classic (eg, limbic encephalitis, cerebellar degeneration), but others have atypical or multifocal presentations. For patients with a suspected paraneoplastic disorder, many and costly oncological evaluations may be required for diagnosis. Comprehensive serological and cerebrospinal fluid (CSF) evaluation for neural autoantibodies may permit a focused cancer evaluation (eg, antineuronal nuclear antibody type 1 [ANNA-1] is associated with small cell lung carcinoma), and in some circumstances may indicate the likelihood of a good response to therapy (eg, voltagegated potassium channel complex antibody) or poor neurological prognosis (eg, purkinje cell cytoplasmic antibody type 1 [antiYo]). Positron-emission tomography-computed tomography (PET-CT) imaging of trunk may increase the diagnostic yield for certain cancers where other modalities have been negative. For some patients, rapid treatment with immunotherapy may facilitate marked improvement, or full recovery; multiple sequential trials of one or more of steroids, intravenous immunoglobulin or plasma exchange, or combination therapy are often required. For patients with N-methyl-D-aspartate receptor antibody encephalitis, early treatment with immunosuppressants and weeks or months of supportive intensive care may additionally be required. One or more of clinical examination, electroencephalogram (including video telemetry), and imaging provide objective parameters to which posttreatment outcomes can be compared.

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Section: Immunotherapymentioning

confidence: 99%

Paraneoplastic and Other Autoimmune Disorders of the Central Nervous System

McKeon

2013

The Neurohospitalist

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“…While a few cases of paraneoplastic SPS have been described in anti-GAD-antibody-positive patients with thymoma and other solid tumors, a finding of anti-GAD antibodies in patients with other classical paraneoplastic neurological syndromes is rare 10,20 . Progressive encephalomyelitis is a rare form of SPS characterized by brainstem, extrapyramidal and spinal cord dysfunction with acute onset of painful rigidity and muscle spasm in association with nystagmus, opsoclonus, ophthalmoparesis, deafness, dysarthria, dysphagia and autonomic dysfunction 21,22 . In our series, there were no cases of paraneoplastic SPS or progressive encephalomyelitis with rigidity.…”

Section: Discussionmentioning

confidence: 99%

“…Some authors recommend actively searching for anti-GAD antibodies in patients with atypical refractory epilepsy either on its own or in association with diabetes mellitus or cerebellar ataxia 25,26 . The heterogeneity of the neurological presentation in patients with neurological syndromes associated with anti-GAD antibodies is probably related to the widespread distribution of GABAergic neurons in the central nervous system as these cells have a large amount of GAD 22 .…”

Section: Discussionmentioning

confidence: 99%

Neurological disorders associated with glutamic acid decarboxylase antibodies: a Brazilian series

Fernandes

Munhoz

Carrilho

et al. 2012

Arq. Neuro-Psiquiatr.

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Neurological disorders associated with glutamic acid decarboxylase (GAD) antibodies include stiff-person syndrome (SPS) and its variants -stiff trunk syndrome, stiff limbs syndrome, progressive encephalomyelitis with rigidity, SPS-plus and paraneoplastic SPS -as well as epilepsy and ataxia [1][2][3][4][5][6][7][8] . These syndromes are often found in association with other autoimmune disorders, such as diabetes mellitus, in more than one thirds of all cases, and, less commonly, those caused by antithyroid, antinuclear and antiparietal cell antibodies (5-10%) [1][2][3][9][10][11][12][13] . GAD is a cytoplasmic enzyme that accelerates the conversion of glutamic acid to gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter present in the brain and spinal cord. GAD is synthesized mainly in presynaptic GABAergic neurons in the central nervous system and in the b cells in the islets of Langerhans in the pancreas. GAD autoantibodies are found in around 60 to 80% of SPS cases. Although there are two GAD isoforms ¾ GAD65 and GAD67 ¾ the main target for GAD autoantibodies in SPS is GAD65 [9][10][11][12][13][14] . The pathogenetic role of autoantibodies in SPS is unclear. However, all SPS autoantigens identified to date are synaptic proteins involved in inhibitory synaptic transmission, such as GAD and amphiphysin (presynaptic antigens) and GABA(A) receptor-associated protein (GABARAP) and gephyrin (postsynaptic antigens). The autoantibodies anti-amphiphysin and anti-gephyrin have been linked to paraneoplastic SPS [9][10][11][12][13][14][15] . The objective of this study was to present the clinical and laboratory findings of 12 patients with neurological disorders associated with anti-GAD antibodies. ABSTRACT Neurological disorders associated with glutamic acid decarboxylase (GAD) antibodies are rare pleomorphic diseases of uncertain cause, of which stiff-person syndrome (SPS) is the best-known. Here, we described nine consecutive cases of neurological disorders associated with anti-GAD, including nine patients with SPS and three cases with cerebellar ataxia. Additionally, four had hypothyroidism, three epilepsy, two diabetes mellitus and two axial myoclonus.

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“…Roughly 25% of GAD65 antibody-positive individuals with these multifocal extrapyramidal symptoms also have limited SPS. 4 Taken together, our patient's cerebellar ataxia, parkinsonian freezing of gait, neck and left leg stiffness, and elevated anti-GAD65 titer suggest a diagnosis of limited SPS (stiff-limb syndrome) in the context of multifocal GAD65 autoimmune neurologic disease.…”

Section: Sectionmentioning

confidence: 99%

“…Antibodies are often also present in the CSF. 4 In contrast, individuals with non-neurologic autoimmune disorders such as diabetes mellitus type 1 or thyroiditis usually have titers less than 20 nmol/L, 10 and antibody-positive individuals without autoimmune disease tend to have titers in the low-positive range (0.03-2 nmol/L).…”

Section: Go To Section 6 E250mentioning

confidence: 99%

Clinical Reasoning: An 82-year-old man with worsening gait

2017

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An 82-year-old man with hypothyroidism presented with difficulty walking.One year prior to presentation, he noticed that his legs occasionally "froze" when initiating walking. His gait progressively worsened over the year. He developed balance difficulty, tripping and falling twice without loss of consciousness. In the 4 months prior to presentation, he started using a cane, a rolling walker, then a wheelchair. He reported occasional neck and left leg cramps. He denied bowel or bladder symptoms.The patient was previously healthy, playing competitive sports at the national level into his late 70s. His only medication was levothyroxine.Question for consideration:1. What examination findings would help to localize the etiology of his abnormal gait?GO TO SECTION 2

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Glutamic Acid Decarboxylase Autoimmunity With Brainstem, Extrapyramidal, and Spinal Cord Dysfunction

Cited by 209 publications

References 38 publications

Paraneoplastic and Other Autoimmune Disorders of the Central Nervous System

Paraneoplastic and Other Autoimmune Disorders of the Central Nervous System

Neurological disorders associated with glutamic acid decarboxylase antibodies: a Brazilian series

Clinical Reasoning: An 82-year-old man with worsening gait

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