Lancet neurology
-
Review
Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. The discovery of genes associated with amyotrophic lateral sclerosis, commencing with SOD1 in 1993, started fairly gradually. Recent advances in genetic technology have led to the rapid identification of multiple new genes associated with the disease, and to a new understanding of oligogenic and polygenic disease risk. ⋯ Of crucial relevance, mutations associated with amyotrophic lateral sclerosis are amenable to novel gene-based therapeutic options, an approach in use for other neurological illnesses. Lastly, the exposome-the summation of lifetime environmental exposures-has emerged as an influential component for amyotrophic lateral sclerosis through the gene-time-environment hypothesis. Our improved understanding of all these aspects will lead to long-awaited therapies and the identification of modifiable risks factors.
-
Spontaneous intracranial hypotension is caused by loss of CSF at the level of the spine. The most frequent symptom of this disorder is orthostatic headache, with the headache worsening in the upright position and subsiding after lying down. Neuroimaging has a crucial role in diagnosing and monitoring spontaneous intracranial hypotension, because it provides objective (albeit often subtle) data despite the variable clinical syndromes and often normal lumbar puncture opening pressure associated with this disorder. ⋯ Searching for a CSF leak can be very difficult; the entire spine must be scrutinised for a dural breach often the size of a pin. Precisely locating the site of CSF leakage is fundamental to successful treatment, which includes a targeted epidural patch and surgical closure when conservative measures do not provide long-term relief. Increased awareness of spontaneous intracranial hypotension among clinicians highlights the need for dedicated diagnostic and therapeutic guidelines.
-
Intracranial atherosclerotic stenosis (ICAS) is one of the most frequent causes of stroke worldwide and confers one of the greatest risks of recurrent stroke compared with other causes of stroke. Asymptomatic ICAS is increasingly recognised as a risk factor for silent brain infarctions and dementia, magnifying the global burden of ICAS. Although ICAS is a lumen-based diagnosis, newer diagnostic imaging techniques, such as high-resolution MRI, might help to identify high-risk population subgroups to test interventions that might reduce the risk of stroke recurrence. ⋯ Despite these therapies, the risk of recurrent stroke in patients presenting with stroke related to 70-99% ICAS exceeds 20% at 1 year; as such, better therapies are urgently needed. The optimal duration and combination of dual antiplatelet therapy in patients with ICAS is uncertain and is being investigated in addition to low-dose anticoagulation and aspirin. Other ongoing or planned studies will provide high-quality observational data on the role of transluminal angioplasty and stenting, submaximal balloon angioplasty alone, direct or indirect arterial bypass, and ischaemic conditioning for prevention of stroke in patients with ICAS.
-
In patients with Parkinson's disease, heterogeneous cholinergic system changes can occur in different brain regions. These changes correlate with a range of clinical features, both motor and non-motor, that are refractory to dopaminergic therapy, and can be conceptualised within a systems-level framework in which nodal deficits can produce circuit dysfunctions. The topographies of cholinergic changes overlap with neural circuitries involved in sleep and cognitive, motor, visuo-auditory perceptual, and autonomic functions. ⋯ Cholinergic system deficits can involve also peripheral organs. Hypercholinergic activity of mesopontine cholinergic neurons in people with isolated rapid eye movement (REM) sleep behaviour disorder, as well as in the hippocampi of cognitively normal patients with Parkinson's disease, suggests early compensation during the prodromal and early stages of Parkinson's disease. Novel pharmacological and neurostimulation approaches could target the cholinergic system to treat motor and non-motor features of Parkinson's disease.
-
Migraine is the second most disabling disorder across all age groups worldwide. Since 2018, two classes of drugs that inhibit the actions of calcitonin gene-related peptide (CGRP), which is implicated in migraine pathophysiology, have become available: gepants (CGRP receptor antagonists) and monoclonal antibodies directed against CGRP or its receptor. Despite phase 3 clinical trials and some real world evidence, knowledge of the pharmacology and related clinical effects of these drugs is low, and trial data are not necessarily generalisable to all populations. ⋯ If studies confirm this possibility, these characteristics could assist clinicians in choosing the optimal treatment for patients with migraine. The choice between a gepant or monoclonal antibody should be made carefully, taking into consideration a patient's comorbidities and preferences. As more becomes known about CGRP-targeted therapies, management based on the characteristics of patients could have a more prominent role in the treatment of migraine.