Design of Phase 3 Studies Evaluating Vixotrigine for Treatment of Trigeminal Neuralgia

Purpose: Vixotrigine (BIIB074) is a voltage- and use-dependent sodium channel blocker. These studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with trigeminal neuralgia (TN) using enriched enrollment randomized withdrawal trial designs. Patients and Methods: Two double-blind randomized withdrawal studies are planned to evaluate the efficacy and safety of vixotrigine compared with placebo in participants with TN (NCT03070132 and NCT03637387). Participant criteria include ≥ 18 years old who have classical, purely paroxysmal TN diagnosed ≥ 3 months prior to study entry, who experience ≥ 3 paroxysms of pain/day. The two studies will include a screening period, 7-day run-in period, a 4- or 6-week single-dose-blind dose-optimization period (Study 1) or 4-week open-label period (Study 2), and 14-week double-blind period. Participants will receive vixotrigine 150 mg orally three times daily in the dose-optimization and open-label periods. The primary endpoint of both studies is the proportion of participants classified as responders at Week 12 of the double-blind period. Secondary endpoints include safety measures, quality of life, and evaluation of vixotrigine population pharmacokinetics. Conclusion: There is a need for an effective, well-tolerated, noninvasive treatment for the neuropathic pain associated with TN. The proposed studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with TN

Spinal Cord Infarction with Multiple Etiologic Factors

Spinal cord infarction is uncommon and usually presents with sudden onset of paralysis and sensory disturbances. A variety of causes are described, but rarely with multiple factors involved. We report a case of a 63-year-old man with a history of diabetes mellitus, hypertension, and osteoarthritis who presented with acute onset of chest pain, numbness, and weakness associated with episodic hypotension. He had incomplete tetraplegia and was areflexic without spasticity. Pain and temperature sensations were impaired below the C7 dermatome and absent below the T4 dermatome bilaterally. Proprioception and vibration sensations were diminished on the right below the C6 dermatome. Magnetic resonance imaging showed spinal cord infarction affecting C6–T3 segments, and severe cervical and lumbar spine degenerative changes. This case illustrates an unusual presenting symptom of spinal infarction, the need to identify multiple risk factors for spinal cord infarction, and the importance of optimal preventive therapy in patients at risk

Stable Isotope Ratios in Hair and Teeth Reflect Biologic Rhythms

Biologic rhythms give insight into normal physiology and disease. They can be used as biomarkers for neuronal degenerations. We present a diverse data set to show that hair and teeth contain an extended record of biologic rhythms, and that analysis of these tissues could yield signals of neurodegenerations. We examined hair from mummified humans from South America, extinct mammals and modern animals and people, both healthy and diseased, and teeth of hominins. We also monitored heart-rate variability, a measure of a biologic rhythm, in some living subjects and analyzed it using power spectra. The samples were examined to determine variations in stable isotope ratios along the length of the hair and across growth-lines of the enamel in teeth. We found recurring circa-annual periods of slow and fast rhythms in hydrogen isotope ratios in hair and carbon and oxygen isotope ratios in teeth. The power spectra contained slow and fast frequency power, matching, in terms of normalized frequency, the spectra of heart rate variability found in our living subjects. Analysis of the power spectra of hydrogen isotope ratios in hair from a patient with neurodegeneration revealed the same spectral features seen in the patient's heart-rate variability. Our study shows that spectral analysis of stable isotope ratios in readily available tissues such as hair could become a powerful diagnostic tool when effective treatments and neuroprotective drugs for neurodegenerative diseases become available. It also suggests that similar analyses of archaeological specimens could give insight into the physiology of ancient people and animals

Stress-related cardiomyopathies

Stress-related cardiomyopathies can be observed in the four following situations: Takotsubo cardiomyopathy or apical ballooning syndrome; acute left ventricular dysfunction associated with subarachnoid hemorrhage; acute left ventricular dysfunction associated with pheochromocytoma and exogenous catecholamine administration; acute left ventricular dysfunction in the critically ill. Cardiac toxicity was mediated more by catecholamines released directly into the heart via neural connection than by those reaching the heart via the bloodstream. The mechanisms underlying the association between this generalized autonomic storm secondary to a life-threatening stress and myocardial toxicity are widely discussed. Takotsubo cardiomyopathy has been reported all over the world and has been acknowledged by the American Heart Association as a form of reversible cardiomyopathy. Four "Mayo Clinic" diagnostic criteria are required for the diagnosis of Takotsubo cardiomyopathy: 1) transient left ventricular wall motion abnormalities involving the apical and/or midventricular myocardial segments with wall motion abnormalities extending beyond a single epicardial coronary artery distribution; 2) absence of obstructive epicardial coronary artery disease that could be responsible for the observed wall motion abnormality; 3) ECG abnormalities, such as transient ST-segment elevation and/or diffuse T wave inversion associated with a slight troponin elevation; and 4) the lack of proven pheochromocytoma and myocarditis. ECG changes and LV dysfunction occur frequently following subarachnoid hemorrhage and ischemic stroke. This entity, referred as neurocardiogenic stunning, was called neurogenic stress-related cardiomyopathy. Stress-related cardiomyopathy has been reported in patients with pheochromocytoma and in patients receiving intravenous exogenous catecholamine administration. The role of a huge increase in endogenous and/or exogenous catecholamine level in critically ill patients (severe sepsis, post cardiac resuscitation, post tachycardia) to explain the onset of myocardial dysfunction was discussed. Further research is needed to understand this complex interaction between heart and brain and to identify risk factors and therapeutic and preventive strategies