Expert Review of Neurotherapeutics最新文献

Introduction: We present a literature review on the clinical conundrums surrounding the differential diagnosis of restless legs syndrome (RLS, Willis-Ekbom disease), as well as conditions that can mimic RLS. An extensive literature search showed that secondary causes of RLS ranged from commonly recognized causes, such as iron deficiency anemia, to less widely noted causes, such as rheumatoid disorders and hypothyroidism. There is a controversial association with Parkinson's disease, essential tremor, and RLS, whereby RLS is proposed as a prodromal feature.

Areas covered: The clinical presentation of restless legs syndrome (RLS), a highly prevalent movement disorder usually during sleep with a circadian variation. The review highlights differences between commonly established secondary causes of RLS, RLS mimics, genetic and drug-induced RLS. A flowchart presents some key features of different and overlapping secondary RLS and mimics and genetic RLS.

Expert opinion: RLS is one of the commonest movement disorders and the International Restless Legs Syndrome Study Group has suggested five-point criteria for robust diagnosis of RLS. However, even in expert hands, diagnosis is accurate in about 85% and misdiagnosis, especially with 'RLS mimics,' appears to be high. There are wide variations in the way RLS can present, and this includes different types of secondary RLS as well as drug induced or genetic patterns of RLS. Secondary RLS is highly complex and can be associated with Parkinson's disease as well as prodromal stage of Parkinson and essential tremor. Other known causes of secondary RLS are many and include end-stage kidney disease as well as metabolic disorders to painful conditions such as rheumatic disorders and fibromyalgia and polyradiculopathy.

Introduction: Cognitive impairment (CI) occurs in 34-70% of multiple sclerosis (MS) patients, significantly impacting quality of life. CI can occur independently of physical disability, even in those with 'benign MS.' Cognitive deficits are heterogeneous, but common areas affected include processing speed, memory, and executive functions.

Areas covered: A comprehensive literature search was conducted across databases such as PubMed and Google Scholar, using keywords like 'MS,' 'cognition,' and 'cognitive rehabilitation.' We focused on clinical assessment tools, emerging cognitive phenotypes, and both pharmacological and non-pharmacological treatments, including disease-modifying therapies and cognitive rehabilitation techniques.

Expert opinion: Current evidence underscores the need for a multifaceted approach to managing CI in MS, incorporating emerging pharmacological treatments, cognitive rehabilitation strategies, and exercise programmes. Future research should prioritize defining optimal training intensities, integrating therapies for sustained cognitive enhancement, and exploring neuromodulation and neuroimaging biomarkers within randomized controlled trials aimed at improving cognitive functioning in MS.

Introduction: In Parkinson's disease (PD), sleep-wake problems are disease-related symptoms that occur throughout the day and have a negative impact on patients' quality of life to an extent that is equal to or greater than that of typical motor symptoms.

Areas covered: Insomnia due to fragmented sleep and excessive daytime sleepiness (EDS) worsen as PD progresses. Nighttime wearing-off and early morning-off should be considered first when fragmented sleep is reported in PD patients. If the main complaint of patients with insomnia is difficulty falling asleep, restless legs syndrome should be differentiated first. Obstructive sleep apnea causes sleep quality deterioration and fragmented sleep. For rapid eye movement sleep behavior disorder (RBD), preventative measures against sleep-related trauma are necessary. RBD has also attracted attention as a PD precursor state and as a disease progression marker that is associated with specific PD clinical subtypes. In PD patients, the sleep-wake phase may advance/delay or become irregular due to circadian dysfunction.

Expert opinion: Importantly, sleep-wake problems are core symptoms related to the pathogenesis and progression of PD, and addressing a wide range of these symptoms will improve patients' quality of life.

Introduction: Cognitive impairment in Parkinson's disease (PD) substantially affects patient outcomes, function, and quality of life. PD-related cognitive dysfunction is often heterogeneous in clinical presentation and rates of progression. As cognitive changes occur in many people with PD, it is essential to evaluate cognition, provide education, and implement management strategies for cognitive symptoms.

Areas covered: This article describes the symptomatology, epidemiology, risk factors, and pathobiology of cognitive impairment in PD. Additionally, the article provides an overview of evidence-based management and other therapeutic and coping strategies for cognitive impairment and dementia in PD. Comment is offered on challenges and opportunities for trials and emerging therapeutics targeting cognitive symptoms or decline.

Expert opinion: While our understanding of cognitive dysfunction in PD has grown, effective and safe therapeutics are still needed to not only treat cognitive impairment and dementia symptomatically but also slow down or prevent cognitive decline. Further research is needed to elucidate the pathobiology of PD cognitive impairment, develop validated biomarkers reflecting cognitive change, and ultimately, integrate clinical and biological frameworks. Consensus regarding cognitive evaluations, definitions, and criteria of cognitive impairment, evaluating functional abilities in the context of cognitive impairment, and determining optimal outcome measures for clinical trials remain unmet needs.

Introduction: Status epilepticus represents a significant neurological emergency, with high morbidity and mortality rates. In addition to standard care, the identification of adjuvant strategies is essential to improve the outcome.

Areas covered: The authors conducted a narrative review to provide an update on the value of hypothermia as an antiseizure and neuroprotective treatment in status epilepticus.

Expert opinion: The use of targeted temperature management in the treatment of hypothermia in patients with status epilepticus represents a potentially promising adjuvant strategy, supported by a substantial body of experimental evidence. However, further clinical data demonstrating its efficacy are necessary before it can be recommended for routine use in targeted patient populations, such as those with refractory or super-refractory status epilepticus.

Introduction: Post-traumatic stress disorder (PTSD) can have debilitating effects on quality of life, and conventional treatments show mixed results. Neuromodulation is emerging as a promising approach for treating PTSD. This review examines current neuromodulatory treatments for PTSD, and highlights methodologies, clinical outcomes, and gaps in the literature to help guide future research.

Areas covered: A PubMed search identified 252 studies on PTSD and neuromodulation, of which 61 were selected for full review. These included 37 studies on repetitive transcranial magnetic stimulation (rTMS), 10 on transcranial direct current stimulation (tDCS),4 on deep brain stimulation (DBS) and 2 on focused ultrasound (FUS).

Expert opinion: The present review supports the potential of neuromodulation to reduce PTSD symptoms. rTMS and tDCS targeting the dlPFC appear effective through modulating neural circuits involved in fear processing and conditioning, however, literature varies regarding efficacy of stimulation frequencies and hemispheric targets. DBS targeting the amygdala or subcallosal cingulate white matter tracts improves treatment of refractory PTSD with sustained benefits, while FUS may improve symptoms through targeted modulation of brain structures such as the amygdala, though this technique is in the early stages of exploration. Future research should refine established neuromodulatory approaches and address gaps in emerging modalities to enhance treatment efficacy.

Introduction: The seizures in Lennox-Gastaut syndrome are typically resistant to treatment. Seven antiseizure medications (ASMs) in the US (six in the UK/EU) are licensed for the treatment of seizures in LGS: lamotrigine, topiramate, rufinamide, clobazam, felbamate (not licensed in the UK/EU), cannabidiol and fenfluramine. Other options include neurostimulation, corpus callosotomy and dietary therapies, principally the ketogenic diet and its variants. New treatments and therapeutic strategies are needed to improve management of both seizures and cognitive/behavioral comorbidities in LGS.

Areas covered: Embase and Medline were searched for articles published between 1 January 2014 and 21 August 2024 reporting efficacy data for pharmacological, neurostimulation, surgical and dietary interventions in individuals with LGS focusing on recent advances. Ongoing and prospective studies were identified from the National Library of Medicine register of clinical trials.

Expert opinion: LGS remains a difficult-to-treat epilepsy. Although no major breakthroughs have been reported, several established and novel ASMs, some surgical strategies and other treatment approaches are of benefit or are showing promise. Progress remains incremental but any improvements in the management of this resistant epilepsy syndrome are worthwhile.

Introduction: Agitation is a common and disruptive syndrome in dementia due to Alzheimer's disease (AD). Brexpiprazole was recently approved for this agitation of AD dementia and is the only therapy approved for this indication.

Areas covered: The authors review the chemistry, pharmacokinetics, mechanism of action, and pharmacodynamics of brexpiprazole. Phase 2/3 and Phase 3 studies of brexpiprazole for the treatment of agitation in dementia due to AD are described. These studies demonstrated efficacy and safety for the 2 mg/d and 3 mg/d doses. Agitation reduction from baseline was significantly greater in the active treatment groups compared to the participants on placebo as measured by the Cohen-Mansfield Agitation Inventory, the primary outcome. Treatment benefit was demonstrated on the Clinician Global Impression - Severity, the key secondary outcome. Safety and tolerability were comparable in drug and placebo arms of the studies.

Expert opinion: Approval by the Food and Drug Administration (FDA) of brexpiprazole for the treatment of agitation in dementia due to AD is an important milestone and regulatory precedent. This is the first approval for the treatment of any neuropsychiatric syndrome of AD. Brexpiprazole has a 'black box' warning for its use in psychosis caused by dementia due to an observed increase in mortality when using this class of antipsychotic agents in patients with dementia. Post-marketing surveillance will be key to understanding the safety profile of brexpiprazole. Brexpiprazole may be prioritized over the 'off label' use of other potential treatments for agitation.

Introduction: The main treatment options for essential tremor (ET), which is probably one of the most common movement disorders, have been propranolol and primidone, for many years. This review aims to synthesize therapeutic attempts with other drugs.

Areas covered: We have reviewed the current state of the pharmacological treatment of ET, both in patients and in experimental models of this disease, with special emphasis on the data published in the last 5 years. Based on the results in experimental models of ET, proposals have been made for future alternative therapeutic options.

Expert opinion: The use of drugs other than propranolol and primidone has not shown a greater degree of efficacy than these in the treatment of ET, although according to certain evidence-based guidelines topiramate and phenobarbital could be alternative drugs. The results on the effectiveness of other drugs have been variable. For patients with refractory ET, especially those with head tremor, local injections with botulinum toxin A may be useful. According to the results of various experimental models, T calcium channel blockers, modulators of GABAA receptors (GABAARs), GABAB receptors (GABABRs), and glutamatergic neurotransmission, and drugs that decrease the expression of LINGO-1 could be interesting options for the future, among others.