Intracerebroventricular delivery of vascular endothelial growth factor in patients with amyotrophic lateral sclerosis, a phase I study.

We studied the feasibility, safety, tolerability and pharmacokinetics of intracerebroventricular delivery of recombinant human vascular endothelial growth factor in patients with amyotrophic lateral sclerosis. In this phase I study in patients with amyotrophic lateral sclerosis, the study drug was delivered using an implantable programmable pump connected to a catheter inserted in the frontal horn of the lateral cerebral ventricle. A first cohort received open label vascular endothelial growth factor (0.2, 0.8 and 2 µg/day), a second cohort received placebo, 0.8 or 2 µg/day of study dug. After the 3-month study period, all patients could participate in an open label extension study. In total, 18 patients with amyotrophic lateral sclerosis, seen at the University Hospitals in Leuven were included. The surgical procedure was well tolerated in most patients. One patient had transient postoperative seizures, due to an ischemic lesion along the catheter tract. The first 3-month study period was completed by 15/18 patients. Administration of 2 µg/day vascular endothelial growth factor resulted in sustained detectable levels in cerebrospinal fluid. A pulmonary embolus occurred in 3 patients, in 1 patient in the first 3-month study, and in 2 patients during the open label extension study. The study drug was well tolerated in the other patients, for up to 6 years in the open label extension study. Our study shows that intracerebroventricular administration of 2 µg/day of vascular endothelial growth factor to patients with amyotrophic lateral sclerosis is feasible, results in detectable cerebrospinal fluid levels and is well tolerated in most patients. The most common serious adverse event was a pulmonary embolus.

Prognostic value of clinical and electrodiagnostic parameters at time of diagnosis in patients with amyotrophic lateral sclerosis.

OBJECTIVE: To assess the added prognostic value of the aggregated clinical and electrodiagnostic data, which define a given diagnostic category according to the Awaji or revised El Escorial criteria at time of diagnosis in patients with amyotrophic lateral sclerosis (ALS). METHODS: Clinical signs and electrodiagnostic test results were collected at time of diagnosis in 396 patients with ALS between January 2009 and January 2016. Significant predictors of prognosis were identified using a univariate model, and later combined in a multivariate Cox regression model. RESULTS: Known factors associated with reduced survival included older age at onset, shorter diagnostic delay, higher ALSFRS-R slope and presence of C9orf72 mutation (all p < 0.05). Diagnostic category according to Awaji (p < 0.0001) or to revised El Escorial (p = 0.0177) criteria, definite ALS according to Awaji (p < 0.0001) or to revised El Escorial (p = 0.0343) and number of regions with LMN involvement (p < 0.0001) were all associated with shorter survival. DISCUSSION: Clinical and electrodiagnostic data at time of diagnosis provide additional prognostic information compared to other known prognostic factors. Diagnostic category according to Awaji and the extensiveness of LMN involvement contain the most additional value.

Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease.

OBJECTIVE: To determine the diagnostic performance and prognostic value of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) in CSF as possible biomarkers for amyotrophic lateral sclerosis (ALS) at the diagnostic phase. METHODS: We measured CSF pNfH and NfL concentrations in 220 patients with ALS, 316 neurologic disease controls (DC), and 50 genuine disease mimics (DM) to determine and assess the accuracy of the diagnostic cutoff value for pNfH and NfL and to correlate with other clinical parameters. RESULTS: pNfH was most specific for motor neuron disease (specificity 88.2% [confidence interval (CI) 83.0%-92.3%]). pNfH had the best performance to differentially diagnose patients with ALS from DM with a sensitivity of 90.7% (CI 84.9%-94.8%), a specificity of 88.0% (CI 75.7%-95.5%) and a likelihood ratio of 7.6 (CI 3.6-16.0) at a cutoff of 768 pg/mL. CSF pNfH and NfL levels were significantly lower in slow disease progressors, however, with a poor prognostic performance with respect to the disease progression rate. CSF pNfH and NfL levels increased significantly as function of the number of regions with both upper and lower motor involvement. CONCLUSIONS: In particular, CSF pNfH concentrations show an added value as diagnostic biomarkers for ALS, whereas the prognostic value of pNfH and NfL warrants further investigation. Both pNfH and NfL correlated with the extent of motor neuron degeneration. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that elevated concentrations of CSF pNfH and NfL can accurately identify patients with ALS.

The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis.

BACKGROUND: Twenty percent of familial amyotrophic lateral sclerosis (ALS) is caused by mutations in the superoxide dismutase 1 gene (SOD1). Few data exist on their clinicopathologic phenotypes. OBJECTIVES: To determine the clinical and pathologic phenotype associated with the G93C mutation in SOD1 and to compare survival in familial ALS related to this mutation with survival in other ALS subgroups. DESIGN: Retrospective study. SETTING: Tertiary referral center for neuromuscular disorders. PATIENTS: Twenty patients with the G93C mutation for whom clinical data were available and 1 patient with pathologic data. MAIN OUTCOME MEASURES: Characteristics and survival compared with other ALS subgroups, adjusting for known prognostic factors. RESULTS: The G93C mutation was associated with a purely lower motor neuron phenotype without bulbar involvement. Presence of the mutation independently predicted longer survival compared with other ALS subgroups. Pathologic examination showed degeneration of the anterior horn, spinocerebellar tracts, and posterior funiculi, with minimal involvement of corticospinal tracts and no degeneration of brainstem motor nuclei. Survival motor neuron gene copy number had no significant influence on age at onset or survival in patients with the G93C mutation. CONCLUSIONS: These findings add to the knowledge of SOD1-related familial ALS and demonstrate further clinicopathologic variability between different SOD1 mutations. Finally, they demonstrate the independent prognostic value of the G93C mutation.

Minocycline delays disease onset and mortality in a transgenic model of ALS.

Microglial activation is thought to contribute to the progression of selective motor neuron death during amyotrophic lateral sclerosis (ALS). As minocycline has been shown to inhibit microglial activation, the therapeutic efficacy of this tetracycline derivative in the G93A mice model for familial ALS was tested. This drug with proven safety delayed disease onset and dose-dependently extended the survival of the G93A mice. At 120 days of age, minocycline protected mice from loss of motor neurons and from vacuolization. These results demonstrate that interference with immuno-inflammatory responses has a beneficial effect in the ALS mice model, suggesting this to be a potential new strategy to treat ALS.