Functional Neurologic Disorders (FNDs) are prevalent in neurology and emergency settings, causing significant disability and economic burden. Diagnosis relies on positive clinical signs rather than exclusion of organic diseases. Treatment includes education, physiotherapy, and cognitive behavioral therapy, although evidence for efficacy is mixed with the few placebo-controlled trials available. The role of placebo in FNDs is debated, with anecdotal cases and a few studies suggesting therapeutic benefits and possible shared pathways between placebo effect and FND symptoms. Ethical concerns relate to deception versus beneficence, especially given limited treatment access.

The nocebo effect has a significant impact on clinical trials and patient care. It leads to more frequent reports of adverse events, higher drop-out rates, and biased judgements of treatment efficacy. This review summarizes the findings from different disease areas and highlights the importance of psychological factors in treatment outcomes. Effective communication, patient awareness, and understanding of nocebo effects are critical to minimizing these reactions, improving patient adherence, and increasing the validity of clinical trials. Dealing with nocebo side effects is critical to optimizing patient care and treatment success.

This review article summarizes key aspects of the placebo response in analgesic trials, including its magnitude across pain syndromes, variation with treatments, and predictors of its strength. It also explores the challenges of distinguishing true therapeutic effects from placebo responses and discusses ethical strategies for leveraging placebo mechanisms in clinical practice. By addressing these issues, the author aims to underscore the complex role the placebo response plays in shaping both the scientific understanding of pain and the clinical approaches used to manage it.

The authors identified and meta-analyzed 84 acute and 42 prophylactic systematically selected RCTs on antimigraine drugs between 1988 and 2024, with a total of 25,542 placebo recipients, analyzed separately for episodic and chronic migraine in adults and children. Placebo response rates in adults were 13% for "Pain Free" and 35% for "Pain Relief" in acute RCTs, and a reduction of -2.83 "monthly migraine days" and -3.64 "monthly headache days" in prophylactic RCTs was observed. The "≥50% responder rate for monthly migraine days" was 28%. In children, placebo responses were almost twice as high. Other important determinants of placebo response were the stringency of the endpoint definition (the milder, the higher), the migraine subtype, and the route of administration. Most acute and older prophylactic RCTs did not meet current strict reporting standards and analysis requirements. This may have biased placebo responses and should be addressed in future studies.

This article explores methods to ethically harness the placebo effect in clinical practice, emphasizing the importance of context, the therapeutic relationship, and patient expectations. It discusses 5 strategies: improving clinician-patient interactions, open-label placebo, conditioned open-label placebo, personalized "n-of-1" trials, and informing patients about nocebo effects to reduce side effects. While evidence supports their efficacy, only the nocebo-informed approach is currently feasible for routine use, due to fewer barriers. The article highlights the potential of these methods to enhance treatment outcomes ethically and calls for systemic support, including from pharmaceutical and health care institutions, to facilitate broader adoption.

Parkinson's disease is well documented to be associated with a placebo response. The striatonigral degeneration and resulting dopamine deficiency make it a particularly compelling condition for studying placebo effects, which are most commonly explained by a hyperdopaminergic hypothesis. The placebo response can vary across different motor and nonmotor symptoms. Several factors may influence this response, including symptom severity, the presence of motor fluctuations, expectation of benefit, and the type of intervention. While minimizing placebo effects is essential in clinical trials-where strategies exist to reduce bias-a placebo response can be leveraged in clinical practice to improve patient outcomes.

The development of novel, rapid-acting treatments and the resurgence of interest in the therapeutic potential of psychedelic-like compounds has stimulated excitement and enthusiasm within the pharmaceutical industry, and provided new hope for millions of individuals suffering with mental illness such as major depressive disorder and post-traumatic stress disorder. This review summarizes the scope and mechanisms of placebo related effects in depression treatment trials, with a particular focus on their implications for psychedelic-like compounds. We examine how expectancy, therapeutic setting, and trial design interact to shape outcomes and consider emerging approaches for mitigating, measuring, or even harnessing placebo-effects in future research.

Epilepsy is a widespread neurologic illness with high morbidity. Further treatments are needed to limit ongoing injury. To demonstrate effectiveness of new treatments, randomized controlled trials comparing adjuvant treatment to placebo are used. Larger placebo response limits trial sensitivity to an effective drug. Placebo also influences many other aspects of epilepsy, including intracranial electroencephalography, nocebo, device treatments, among others. Recent advances in modeling suggest that a true placebo effect in epilepsy treatment trials is possibly nil and that placebo response may be due to natural fluctuation alone, although further studies are necessary.

Dealing with placebo responses in randomized controlled trials for multiple sclerosis presents significant challenges. In studies evaluating both disease-modifying therapies and treatments for symptoms such as spasticity and fatigue, considerable improvements are frequently observed in the placebo arm, with this phenomenon becoming more pronounced in recent studies. Several mechanisms may influence placebo responses, with important implications for trial design and data interpretation. Changes in trial populations due to evolving diagnostic criteria, patient expectations, study design, and the type of treatment or placebo employed, are key factors that should be carefully considered to interpret the results.

Placebo response is different from the placebo effect. Whereas the placebo response is the global response to a placebo, including spontaneous remission, regression to the mean, patients' and experimenters' biases, as well as psychological factors, the placebo effect includes only the psychological factors, such as patients' expectations and learning. It is like the difference between drug response and drug effect, whereas the former is the global response to a drug, the latter represents the specific pharmacodynamic effect. Nocebo responses and nocebo effects go in the opposite direction; these consist in the experience of adverse events when a placebo is administered.

This article reviews the epidemiology and clinical characteristics necessary to make the diagnosis of cryptogenic sensory polyneuropathy (CSPN). This article also discusses the metabolic syndrome and other possible etiologies of neuropathy that need to be excluded before considering the diagnosis of CSPN. Most of the diagnostic testing performed for autoimmune neuropathies and hereditary neuropathies are not necessary to make the diagnosis. Treatment is mostly symptomatic and autoimmune therapies do not have any role in the management of CSPN patients.

Guillain-Barré syndrome (GBS) is an acute immune-mediated polyneuropathy that leads to rapidly progressive weakness and, in up to 20% of cases, respiratory failure. GBS is a heterogeneous disorder with varying phenotypic presentations, electrophysiologic features, and outcomes. Plasma exchange and intravenous immunoglobulin can help reduce the time to recovery, in addition to improving ventilatory function and mobility. New treatments, such as C1q complement-blocking antibodies, are currently under study and may improve outcomes in the future. This article provides an overview of the epidemiology, clinical symptoms, causes, diagnostic methods, treatment options, and prognosis of GBS.

Cryptogenic or idiopathic sensory polyneuropathy (CSPN) is a common type of neuropathy seen in patients aged usually older than 50 years. Symptoms and signs are predominantly sensory while motor manifestations are usually mild or absent. Extensive evaluation usually does not reveal a clear identifiable laboratory testing abnormality or electrophysiology testing abnormality. Skin biopsy may be helpful in some patients. This article reviews the etiologies and varied presentation of nutritional neuropathies. Specific syndromes of both nutritional deficiency and excess are reviewed with attention toward epidemiology, risk factors, prevention, and treatment.

A pattern recognition approach to autoimmune polyneuropathies is fundamental to an evidence-based, efficient, and cost-effective approach to the accurate diagnosis of such chronic inflammatory demyelinating polyneuropathy mimickers as multifocal motor neuropathy, autoimmune nodopathies, anti-myelin associated glycoprotein neuropathy, chronic inflammatory sensory polyradiculoneuropathy, and chronic ataxic neuropathy with ophthalmoplegia, M-protein, agglutinin, and disialosyl antibodies. Increased understanding of the IgG4 and IgG3 mediated autoimmune nodopathies represents an exciting advance in our pathomechanistic understanding of immune mediated polyneuropathy that defies the traditional axonal vs demyelinating construct, and rather, reflects targeted dysfunction of the node of Ranvier.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the prototypic chronic inflammatory polyneuropathy, characterized by well-defined clinical and electrodiagnostic criteria, despite the absence of biomarkers or full understanding of disease pathogenesis. It has both a typical form and 5 variants. IVIG remains the treatment of choice for induction or maintenance of remission, although corticosteroids, plasma exchange, and most recently, efgartigimod, demonstrate therapeutic efficacy. Subcutaneous immunoglobulin is indicated only as maintenance therapy. Validated outcome measures exist to track disability, strength, and quality of life and should be routinely employed in clinical practice.

Vasculitic neuropathies are a group of disorders characterized by inflammation and destruction of vessel walls, resulting in nerve ischemic injury that leads to acute-to-subacute sensory and motor deficits. This can arise from systemic inflammation or be confined to the peripheral nervous system. Causes include primary systemic vasculitis, secondary vasculitis associated with connective tissue disorders, viral infections, paraneoplastic and drug-induced reactions, and nonsystemic vasculitic neuropathy. Early recognition and prompt treatment are essential to mitigate the morbidity and mortality associated with these disorders. This review provides an update on the classification, diagnosis, and treatment of vasculitic neuropathies.

Inherited peripheral neuropathies are a diverse group of genetic disorders marked by progressive degeneration of peripheral motor, sensory, and autonomic nerves. While next-generation sequencing has improved diagnosis, challenges remain, including resolving variants of uncertain significance and addressing 20% to 50% of inherited neuropathy cases without clear diagnoses. Current care for inherited neuropathies focuses on supportive therapies to preserve functional range of motion, strength, and balance. Research into disease-modifying treatments is advancing, but accelerating progress requires continued biomarker discovery and innovative drug delivery strategies. This article highlights the clinical features, diagnostic approaches, treatment options, and emerging research in the field.

Amyloidosis is a potentially treatable cause of polyneuropathy with various distinct etiologies, including amyloid light chain (AL), transthyretin variant (ATTRv), wild-type transthyretin amyloidosis (wrATTR), gelsolin, and apolipoprotein A1 (ApoA-I). Among these, AL and transthyretin amyloidosis are the most common, while AGel and ApoA-I amyloidosis present more complex diagnostic challenges due to their rarity. Despite advances in the recognition and treatment of AL and transthyretin amyloid protein amyloidosis, diagnostic delays remain a concern. Accurate diagnosis hinges on genetic testing, biomarker development, and tissue biopsy with Congo red staining. Multidisciplinary collaboration, including neurologists, is crucial for optimizing patient outcomes across all forms of amyloidosis.

The peripheral autonomic nervous system regulates the automatic, typically involuntary processes of the body under neural control. As with other types of polyneuropathy, autonomic neuropathies may arise from a variety of causes. Autonomic neuropathies may be generalized (global) or selective (affecting a single or few autonomic functions). Clinical diagnosis of autonomic neuropathies relies primarily on an appropriate clinical history incorporating an autonomic review of systems. Many cases of autonomic neuropathy remain idiopathic. When an underlying cause of autonomic neuropathy can be identified, it should be treated. In many cases of autonomic neuropathy, treatment is primarily symptomatic.