Early versus delayed treatment with glatiramer acetate: Analysis of up to 27 years of continuous follow-up in a US open-label extension study.

BACKGROUND: Glatiramer acetate (GA) is US-approved for relapsing multiple sclerosis. OBJECTIVES: To describe GA long-term clinical profile. To compare effectiveness of early start (ES) versus delayed start (DS; up to 3 years) with GA. METHODS: Phase 3 trial participants entered a randomized placebo-controlled period then an open-label extension (OLE) with GA. RESULTS: Overall, 208 out of 251 (82.9%) randomized participants entered the OLE; 24 out of 101 (23.8%, ES) and 28 out of 107 (26.2%, DS) participants completed the OLE. Median GA treatment was 9.8 (0.1-26.3) years. Annualized change in Expanded Disability Status Scale (EDSS) score was lower with ES versus DS (p = 0.0858: full study; p = 0.002; Year 5). Participants with improved/stable EDSS was consistently higher with ES versus DS: 40.3% versus 31.6% (p = 0.1590; full study); 70.8% versus 55.6% (p = 0.015; Year 5). ES prolonged time-to-6-month confirmed disease worsening (CDW) versus DS (9.8 vs 6.7 years), time-to-12-month CDW (18.9 vs 11.6 years), and significantly reduced time-to-second-6-month CDW (p = 0.0441). No new safety concerns arose. CONCLUSION: GA long-term treatment maintained clinical benefit with a similar safety profile to phase 3 results; a key limitation was that only 25% of participants completed the OLE. Early initiation of GA had sustained benefits versus delayed treatment.

Safety and efficacy of helminth treatment in relapsing-remitting multiple sclerosis: Results of the HINT 2 clinical trial.

BACKGROUND: The hygiene hypothesis suggests that microbial replacement may be therapeutic in allergic and autoimmune diseases. Nevertheless, the results of helminth treatment, including in multiple sclerosis (MS), have been inconclusive. OBJECTIVE: To assess safety and brain magnetic resonance imaging (MRI) activity in subjects with relapsing-remitting multiple sclerosis (RRMS) during oral administration of ova from the porcine whipworm, Trichuris suis (TSO). METHODS: A total of 16 disease-modifying treatment (DMT) naive RRMS subjects were studied in a baseline versus treatment (BVT) controlled prospective study. MRI scans were performed during 5 months of screening-observation, 10 months of treatment, and 4 months of post-treatment surveillance. RESULTS: No serious symptoms or adverse events occurred during treatment. For the cohort, there was a trend consistent with a 35% diminution in active lesions when observation MRIs were compared to treatment MRIs ( p = 0.08), and at the level of individuals, 12 of 16 subjects improved during TSO treatment. T regulatory lymphocytes were increased during TSO treatment. CONCLUSION: TSO is safe in RRMS subjects. Potentially favorable MRI outcomes and immunoregulatory changes were observed during TSO treatment; however, the magnitude of these effects was modest, and there was considerable variation among the responses of individual subjects.

Ventriculoperitoneal Shunt Drainage Increases With Gravity and Cerebrospinal Fluid Pressure Pulsations: Benchtop Model.

BACKGROUND: There have been few improvements in cerebrospinal fluid (CSF) shunt technology since John Holter introduced the silicon valve, with overdrainage remaining a major source of complications. OBJECTIVE: To better understand why valves are afflicted by supra-normal CSF flow rates. We present in Vitro benchtop analyses of flow through a differential pressure valve under simulated physiological conditions. METHODS: The pseudo-ventricle benchtop valve testing platform that comprises a rigid pseudo-ventricle, compliance chamber, pulsation generator, and pressure sensors was used to measure flow rates through a differential pressure shunt valve under the following simulated physiological conditions: orientation (horizontal/vertical), compliance (low/medium/high), and pulsation generator force (low/medium/high). RESULTS: Our data show that pulse pressures are faithfully transmitted from the ventricle to the valve, that lower compliance and higher pulse generator forces lead to higher pulse pressures in the pseudo-ventricle, and that both gravity and higher pulse pressure lead to higher flow rates. The presence of a valve mitigates but does not eliminate these higher flow rates. CONCLUSION: Shunt valves are prone to gravity-dependent overdrainage, which has motivated the development of gravitational valves and antisiphon devices. This study shows that overdrainage is not limited to the vertical position but that pulse pressures that simulate rhythmic (eg, cardiac) and provoked (eg, Valsalva) physiological CSF pulsations increase outflow in both the horizontal and vertical positions and are dependent on compliance. A deeper understanding of the physiological parameters that affect intracranial pressure and flow through shunt systems is prerequisite to the development of novel valves.

Intracranial Pressure Sensor and Valve to Control Hydrocephalus.

Hydrocephalus is a neurological condition that can result from trauma, hemorrhage, cancer, and infection. To control the intracranial pressure (ICP) a shunt is implanted to drain the cerebro-spinal fluid (CSF). We are working to develop an implantable pressure sensor. When the ICP is too high it will open a valve to relieve the ICP. When the ICP is too low, it will close the valve.

Ventriculoperitoneal shunt perforations of the gastrointestinal tract.

OBJECT The purposes of this study were to evaluate the frequency with which children presented with ventriculoperitoneal (VP) shunt perforations of the gastrointestinal (GI) tract, to determine the type of shunts that caused the perforations, and to compare the stiffness of perforating catheters with the stiffness of catheters from other manufacturers. METHODS Medical records were reviewed of 197 children who were admitted with VP shunt malfunction. Catheter stiffness was evaluated by measuring relative resistance to cross-sectional compression, resistance to column buckling, and elasticity in longitudinal bending. Catheter frictional force was measured per unit length. RESULTS Six children were identified whose VP shunts had perforated the GI tract; 2 shunts subsequently protruded through the anal orifice, 1 protruded through the oral cavity, and 3 presented with subcutaneous abscesses that tracked upward from the intestine to the chest. All perforating shunts were Chhabra shunts. Catheter stiffness and resistance to bending were greatest with a Medtronic shunt catheter, intermediate with a Codman catheter, and least with a Chhabra catheter. Frictional force was greatest with a Chhabra catheter and least with a Medtronic catheter. CONCLUSIONS The frequency of perforations by Chhabra shunts appears to be higher than the frequency associated with other shunts. The increased frequency does not correlate with their stiffness but may reflect their greater frictional forces.

Effects of limb exercise after spinal cord injury on motor neuron dendrite structure.

An integration center subserving locomotor leg movements resides in the upper lumbar spinal cord. If this neuronal network is preserved after a spinal cord injury, it is possible to stimulate this circuitry to initiate and promote walking. The several effective approaches (electrical stimulation, pharmacologic agents, physical therapy training programs) may all share a common modus operandi of altering synaptic activity within segmental spinal cord. To understand the neural substrate for the use-dependent behavioral improvement, we studied the dendritic architecture of spinal motor neurons. In the first experiment, we compared three groups of animals: animals with an intact spinal cord, animals that had a complete spinal cord transection (SCT) and animals with SCT who engaged in a daily exercise program of actively moving paralyzed hindlimbs through the motions of walking. When compared with animals with an intact spinal cord, the motor neurons from animals with SCT displayed marked atrophy, with loss of dendritic membrane and elimination of branching throughout the visible tree within transverse tissue slices. None of these regressive changes were found in the motor neurons from SCT animals that underwent exercise. In a second experiment, we inquired whether exercise of animals with an intact spinal cord influenced dendrite structure. Increased exercise had very modest effects on dendrite morphology, indicating an upper limit of use-dependent dendrite growth. Our findings suggest that the dendritic tree of motor neurons deprived of descending influences is rapidly pruned, and this finding is not observed in motor neurons after SCT if hindlimbs are exercised. The functional benefits of exercise after SCT injury may be subserved, in part, by stabilizing or remodeling the dendritic tree of motor neurons below the injury site.

Myeloneuropathy from nitrous oxide abuse: unusually high methylmalonic acid and homocysteine levels.

A 23-year-old patient developed diffuse paresthesias and sensory loss. He had mildly reduced serum vitamin B12 (B12) concentration with unusually high levels of methylmalonic acid (MMA) and homocysteine and no evidence of B12 malabsorption. Following parenteral B12 administration, his neurological deficit promptly resolved and B12 and MMA levels normalized, but elevated levels of homocysteine persisted. One year later, he admitted to inhaling nitrous oxide (N2O). After halting N2O abuse his homocysteine level normalized. This case demonstrates the importance of serum homocysteine level measurements in cases of suspected N2O toxicity [corrected].

Late onset multiple sclerosis: Is it really late onset?

BACKGROUND: Multiple sclerosis (MS) is the most common demyelinating disease, and onset over the age of 50 years is referred to as late onset MS (LOMS). It has been thought that LOMS patients will be more likely to exhibit a primary progressive (PPMS) clinical course. OBJECTIVE: To identify the clinical characteristics of demyelinating disease in patients over the age of 50 years from four different MS centers in the Northern Midwest USA. METHODS: We reviewed medical records of all patients seen at the MS centers and identified those who were 50 years of age or more at the time of first spontaneously reported symptoms. We included those who were diagnosed with MS or clinically isolated syndrome (CIS) and excluded MS mimickers. Demographics, initial clinical course diagnosis, clinical characteristics, and any available five-year follow up data were collected. The clinical course was reevaluated in each patient with careful questioning regarding any prior focal neurological symptoms that had persisted for at least 48h, not otherwise explained. Those with a prior event who were initially diagnosed with PPMS or CIS were reclassified as secondary-progressive MS (SPMS) and relapsing-remitting MS (RRMS) respectively. RESULTS: We identified 124 patients from a total of 3700 patients, making LOMS 3.4% MS in our population. The initial clinical course was RRMS in 50 (40%), PPMS in 44 (36%), SPMS in 15 (12%), and CIS in 15 (12%) patients. After reclassification the clinical course was RRMS in 55 (44%), PPMS in 25 (20%), SPMS in 34 (28%), and CIS in 10 (8%) patients. The clinical syndrome was identified as acute for 77 patients (62%) with transverse myelitis (N=25, 32%) as the most common type. The clinical syndrome was chronic for 47 patients (37%) and again transverse myelitis (N=24, 51%) was the most common type. Five-year follow up data was available for 44% of these patients. DISCUSSION: LOMS is rare and RRMS is the most common clinical course. Reclassification of the clinical course, not done before in any other LOMS study, with careful questioning regarding a prior neurological event reveals that SPMS is the most common type of progressive MS and PPMS may be less common than previously thought. Transverse myelitis is the most common clinical presentation.

Posture-independent piston valve: a novel valve mechanism that actuates based on intracranial pressure alone.

OBJECT: Shunt valves are intended to maintain physiological intracranial pressure (ICP). A variety of mechanisms have been designed to accomplish this goal but have had limited success. Siphoning, in particular, has been a problem not effectively solved by proposed or manufactured valves. Poor control of ICP results in headache, neurological disturbances, decreased cognition, shunt malfunction, slit ventricles, subdural hematomas, decreased cranial volume, and maldevelopment. The authors of this study describe a prototype valve that was machined and tested ex vivo and that actuates based on ICP alone regardless of the presence of a siphon. Their object was to determine if a novel shunt mechanism that actuates perpendicular to the flow of fluid would eliminate the effect of siphoning in a valve for the treatment of hydrocephalus. METHODS: A posture-independent piston valve (PIPV) was anchored to a graduated reservoir. Opening pressure was measured by noting the fluid level in the reservoir when the piston moved. Measurements were made using a 90-cm and a 120-cm water-filled siphon tube (1.3-mm standard distal catheter) to simulate an upright posture. A recumbent posture was simulated by the absence of a siphon. RESULTS: Opening pressure of the valve did not change regardless of the presence or absence of a water-filled siphon. CONCLUSIONS: The PIPV was triggered only by the pressure head at the inlet and did not actuate in the presence of a siphon, demonstrating proof of principle of the perpendicular actuating mechanism. The PIPV is a purely mechanical device that has practical application in the treatment of hydrocephalus.