Placebo and nocebo effects in the neurological practice

Bittar, Caroline; Nascimento, Osvaldo J. M.

doi:10.1590/0004-282x20140180

Cited by 9 publications

(7 citation statements)

References 31 publications

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“…Indeed, perhaps non-immune causes of neuronal destruction are sufficient to release immunogenic Kv1 antigens and provoke autoantibody production. 16 22 26 Interestingly, the immunotherapy response observed in 27% of patients is very similar to the placebo response rates observed in several other neurological diseases, 37 and much lower than those reported in LGI1 or CASPR2 antibody-associated syndromes. 7–9 11 15 29 35 However, conclusions regarding treatment outcomes are only definitive after blinded interventional studies.…”

Section: Discussionsupporting

confidence: 75%

Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies

Lang

Makuch

Moloney

et al. 2017

J Neurol Neurosurg Psychiatry

130

112

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ObjectivesAutoantibodies against the extracellular domains of the voltage-gated potassium channel (VGKC) complex proteins, leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-2 (CASPR2), are found in patients with limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. However, in routine testing, VGKC complex antibodies without LGI1 or CASPR2 reactivities (double-negative) are more common than LGI1 or CASPR2 specificities. Therefore, the target(s) and clinical associations of double-negative antibodies need to be determined.MethodsSera (n=1131) from several clinically defined cohorts were tested for IgG radioimmunoprecipitation of radioiodinated α-dendrotoxin (125I-αDTX)-labelled VGKC complexes from mammalian brain extracts. Positive samples were systematically tested for live hippocampal neuron reactivity, IgG precipitation of 125I-αDTX and 125I-αDTX-labelled Kv1 subunits, and by cell-based assays which expressed Kv1 subunits, LGI1 and CASPR2.ResultsVGKC complex antibodies were found in 162 of 1131 (14%) sera. 90 of these (56%) had antibodies targeting the extracellular domains of LGI1 or CASPR2. Of the remaining 72 double-negative sera, 10 (14%) immunoprecipitated 125I-αDTX itself, and 27 (38%) bound to solubilised co-expressed Kv1.1/1.2/1.6 subunits and/or Kv1.2 subunits alone, at levels proportionate to VGKC complex antibody levels (r=0.57, p=0.0017). The sera with LGI1 and CASPR2 antibodies immunoprecipitated neither preparation. None of the 27 Kv1-precipitating samples bound live hippocampal neurons or Kv1 extracellular domains, but 16 (59%) bound to permeabilised Kv1-expressing human embryonic kidney 293T cells. These intracellular Kv1 antibodies mainly associated with non-immune disease aetiologies, poor longitudinal clinical–serological correlations and a limited immunotherapy response.ConclusionsDouble-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits and occasionally against non-mammalian αDTX. These antibodies should no longer be classified as neuronal-surface antibodies. They consequently lack pathogenic potential and do not in themselves support the use of immunotherapies.

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Section: Discussionsupporting

confidence: 75%

Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies

Lang

Makuch

Moloney

et al. 2017

J Neurol Neurosurg Psychiatry

130

112

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“…In marked contrast, patients with double-negative VGKC antibodies respond poorly to immunotherapy, with response rates equal to those of placebo studies, or to rates observed from patients with negative VGKC test results. 26 28 44…”

Section: Features Associated With Double-negative Vgkc Antibodiesmentioning

confidence: 99%

Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2

2020

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Autoantibodies to leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein like-2 (CASPR2) are associated with clinically distinctive syndromes that are highly immunotherapy responsive, such as limbic encephalitis, faciobrachial dystonic seizures, Morvan’s syndrome and neuromyotonia. These autoantibodies target surface-exposed domains of LGI1 or CASPR2, and appear to be directly pathogenic. In contrast, voltage-gated potassium channel (VGKC) antibodies that lack LGI1 or CASPR2 reactivities (‘double-negative’) are common in healthy controls and have no consistent associations with distinct syndromes. These antibodies target intracellular epitopes and lack pathogenic potential. Moreover, the clinically important LGI1 and CASPR2 antibodies comprise only ~15% of VGKC-positive results, meaning that most VGKC-antibody positive results mislead rather than help. Further, initial VGKC testing misses some cases that have LGI1 and CASPR2 antibodies. These collective observations confirm that laboratories should stop testing for VGKC antibodies and instead, test only for LGI1 and CASPR2 antibodies. This change in practice will lead to significant patient benefit.

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“…The conditioning mechanism is evident when the patient experienced negative results with previous other drugs. [ 9 ]…”

Section: What It Means In Clinical Practice?mentioning

confidence: 99%

Minimizing nocebo effect: Pragmatic approach

2017

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The nocebo effect, the inverse of the placebo effect, is a well-established phenomenon, yet under-appreciated. It refers to nonpharmacological, harmful, or undesirable effects occurring after active or inactive therapy. The frequency of adverse events can dramatically increase by informing patients about the possible side effects of the treatment, and by negative expectations on the part of the patient. Patients who were told that they might experience sexual side effects after treatment with β-blocker drugs reported these symptoms between three and four times more often than patients in a control group who were not informed about these symptoms. Nocebo effect has been reported in several neurological diseases such as migraine, epilepsy, multiple sclerosis, Parkinson's disease and neuropathic pain, and in patients with depression. The investigation of the biological and theoretical underpinning of the nocebo phenomenon is at an early stage, and more research is required. Physicians need to be aware of the influence of nocebo phenomenon and be able to recognize it and minimize its effects.

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Placebo and nocebo effects in the neurological practice

Cited by 9 publications

References 31 publications

Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies

Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies

Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2

Minimizing nocebo effect: Pragmatic approach

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