Proximal Intracranial Arterial Occlusions Does the Natural History Justify Further Interventional Trials?

Over the past 2 decades, the treatment of acute ischemic stroke has undergone significant changes. The National Institute of Neurological Disorders and Stroke tissue plasminogen activator study1 in 1995 followed by the third European Cooperative Acute Stroke Study (ECASS III)2 in 2008 heralded major breakthroughs in the hyperacute management of patients with ischemic stroke. Yet despite the promise of these landmark studies, the overall use of intravenous tissue plasminogen activator remained meager, reaching less than 5% of all stroke patients in the United States through 2006.3 Furthermore, for certain stroke subtypes, such as those with proximal intracranial arterial occlusions, the rate of recanalization remained low,4 resulting in poor outcomes when early recanalization was not achieved

The emerging agenda of stratified medicine in neurology

In this Review, Paul Matthews and colleagues outline the potential benefits of a stratified approach to health-care delivery in neurology, including reduced risk of adverse events from medicines, and lower treatment costs. They provide examples of neurological diseases in which stratified medicine is already improving treatment, and consider challenges to implementation of these approaches.

Nature Reviews Neurology

Neurodegenerative disease: Mapping the natural history of Huntington disease

A key challenge to improving the design of clinical trials in Huntington disease (HD) has been the limited data on the natural history of HD. A recent prospective longitudinal study has provided important information in this regard, which could be useful for future translation of disease-modifying therapies for early-stage HD.

Nature Reviews Neurology 2013

The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48 362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10⁻¹²). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10⁻¹²). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.

Brain 2013

Variant nonketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5

Patients with nonketotic hyperglycinemia and deficient glycine cleavage enzyme activity, but without mutations in AMT, GLDC or GCSH, the genes encoding its constituent proteins, constitute a clinical group which we call ‘variant nonketotic hyperglycinemia’. We hypothesize that in some patients the aetiology involves genetic mutations that result in a deficiency of the cofactor lipoate, and sequenced genes involved in lipoate synthesis and iron-sulphur cluster biogenesis. Of 11 individuals identified with variant nonketotic hyperglycinemia, we were able to determine the genetic aetiology in eight patients and delineate the clinical and biochemical phenotypes. Mutations were identified in the genes for lipoate synthase (LIAS), BolA type 3 (BOLA3), and a novel gene glutaredoxin 5 (GLRX5). Patients with GLRX5-associated variant nonketotic hyperglycinemia had normal development with childhood-onset spastic paraplegia, spinal lesion, and optic atrophy. Clinical features of BOLA3-associated variant nonketotic hyperglycinemia include severe neurodegeneration after a period of normal development. Additional features include leukodystrophy, cardiomyopathy and optic atrophy. Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement. All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio, and deficient glycine cleavage enzyme activity. They had low pyruvate dehydrogenase enzyme activity but most did not have lactic acidosis. Patients were deficient in lipoylation of mitochondrial proteins. There were minimal and inconsistent changes in cellular iron handling, and respiratory chain activity was unaffected. Identified mutations were phylogenetically conserved, and transfection with native genes corrected the biochemical deficiency proving pathogenicity. Treatments of cells with lipoate and with mitochondrially-targeted lipoate were unsuccessful at correcting the deficiency. The recognition of variant nonketotic hyperglycinemia is important for physicians evaluating patients with abnormalities in glycine as this will affect the genetic causation and genetic counselling, and provide prognostic information on the expected phenotypic course.

Brain 2013

Optic neuritis

Acute optic neuritis is the most common optic neuropathy affecting young adults. Exciting developments have occurred over the past decade in understanding of optic neuritis pathophysiology, and these developments have been translated into treatment trials. In its typical form, optic neuritis presents as an inflammatory demyelinating disorder of the optic nerve, which can be associated with multiple sclerosis. Atypical forms of optic neuritis can occur, either in association with other inflammatory disorders or in isolation. Differential diagnosis includes various optic nerve and retinal disorders. Diagnostic investigations include MRI, visual evoked potentials, and CSF examination. Optical coherence tomography can show retinal axonal loss, which correlates with measures of persistent visual dysfunction. Treatment of typical forms with high-dose corticosteroids shortens the period of acute visual dysfunction but does not affect the final visual outcome. Atypical forms can necessitate prolonged immunosuppressive regimens. Optical coherence tomography and visual evoked potential measures are suitable for detection of neuroaxonal loss and myelin repair after optic neuritis. Clinical trials are underway to identify potential neuroprotective or remyelinating treatments for acutely symptomatic inflammatory demyelinating CNS lesions.

Lancet Neurology 2013

Vasculitic Neuropathies

The vasculitic neuropathies are a diverse group of disorders characterised by the acute-to-subacute onset of painful sensory and motor deficits that result from inflammatory destruction of nerve blood vessels and subsequent ischaemic injury. They are common in patients with primary systemic vasculitis and are seen in vasculitis secondary to disorders such as rheumatoid arthritis, viral infections, and diabetic inflammatory neuropathies. It is imperative that neurologists recognise these disorders to initiate treatment promptly and thereby prevent morbidity and mortality. To simplify the approach to patients with vasculitis of the peripheral nerves, a straightforward, dichotomous classification scheme can be used in which the vasculitic neuropathies are divided into two groups—nerve large arteriole vasculitis and nerve microvasculitis—on the basis of the size of the involved vessels. The size of the affected blood vessels correlates with the clinical course and prognosis in patients with vasculitic neuropathy.

Lancet Neurology 2013