Lawrence H. Phillips

The unchanging pattern of subarachnoid hemorrhage in a community

The average annual incidence of subarachnoid hemorrhage (SAH) from aneurysm rupture in Rochester, Minnesota, has remained remarkably constant at about 11 per 100,000 population. Age-specific incidence increased with age. Survival after SAH depended on: (1) clinical grade, (2) time after onset of SAH, and (3) presence of intracerebral hematoma. Among those who survived to receive medical attention, 48% were clinical grade 1 or 2, 20% were grade 3, and 32% were grade 4 or 5. Proved rebleeding occurred within 10 days of the first SAH in 20% of patients who survived until hospital admission.

Mitochondria in Sporadic Amyotrophic Lateral Sclerosis

Mitochondria are abnormal in persons with amyotrophic lateral sclerosis (ALS) for unknown reasons. We explored whether aberration of mitochondrial DNA (mtDNA) could play a role in this by transferring mitochondrial DNA (mtDNA) from ALS subjects to mtDNA-depleted human neuroblastoma cells. Resulting ALS cytoplasmic hybrids (cybrids) exhibited abnormal electron transport chain functioning, increases in free radical scavenging enzyme activities, perturbed calcium homeostasis, and altered mitochondrial ultrastructure. Recapitulation of defects previously observed in ALS subjects and ALS transgenic mice by expression of ALS mtDNA support a pathophysiologic role for mtDNA mutation in some persons with this disease.

Hypnotic analgesia reduces R-III nociceptive reflex: further evidence concerning the multifactorial nature of hypnotic analgesia.

&NA; Mechanisms of hypnotic analgesia were investigated by examining changes in the R‐III, a nociceptive spinal reflex, during hypnotic reduction of pain sensation and unpleasantness. The R‐III was measured in 15 healthy volunteers who gave VAS‐sensory and VAS‐affective ratings of an electrical stimulus during conditions of resting wakefulness, suggestions for hypnotic analgesia, and attempted suppression of the reflex during non‐hypnotic conditions. The H‐reflex was also measured to monitor and control for general changes in alpha‐motoneuron excitability. Hypnotic sensory analgesia was related to reduction in the R‐III after controlling for changes in the H‐reflex (R2 = 0.51, P < 0.003), suggesting that hypnotic sensory analgesia is at least in part mediated by descending antinociceptive mechanisms that exert control at spinal levels in response to hypnotic suggestion. The relationship between hypnotic affective analgesia and reduction in R‐III approached significance (R2 = 0.26; P = 0.053). Reduction in R‐III was 67% as great and accounted for 51% of the variance in reduction of pain sensation. In turn, reduction in pain sensation was 75% as great and accounted for 77% of the variance in reduction of unpleasantness. The results suggest that 3 general mechanisms may be involved in hypnotic analgesia. The first, implicated by reductions in R‐III, is related to spinal cord antinociceptive mechanisms. The first, implicated by pain sensation over and beyond reductions in R‐III, may be related to brain mechanisms that serve to prevent awareness of pain once nociception has reached higher centers, as suggested by Hilgard. The third, implicated by reductions in unpleasantness over and beyond reductions in pain sensation, may be related to selective reduction in the affective dimension, possibly as a consequence of reinterpretation of meanings associated with the painful sensation. Hypnotic suggestions for sensory analgesia were not more effective in reducing pain sensation, unpleasantness, or the R‐III than were hypnotic suggestions for comfort and well‐being. A moderate correlation was found between hypnotic susceptibility and sensory analgesia (Tau B = 0.45; P < 0.01), but no significant correlations were found between susceptibility and affective analgesia (Tau B = 0.27; P = 0.08), or between susceptibility and hypnotic reduction of R‐III (Tau B = 0.27; P = 0.1).

The epidemiology of myasthenia gravis in central and western Virginia

We conducted a study of the epidemiology of myasthenia gravis (MG) in four locations in central and western Virginia from 1970 through 1984. The population surveyed was 555,851 in 1984. A total of 73 new cases of MG occurred during the survey period, producing an overall average annual incidence rate of 9.1 per million. The point prevalence rate in 1980 was 13.4 per 100,000, and in 1984 it was 14.2. Approximately 15% of the population was black, and we found that incidence and prevalence rates for the black population were higher than the corresponding white population. When the population was subdivided into <50 and 50+ age groups, the incidence and prevalence were significantly higher in the older group. The rates we report here are higher than rates reported from any other locality. The reasons for the higher rates include optimal case identification, survey of a population with a higher incidence, and increasing aging of the population.

CLINICAL FINDINGS IN MUSK-ANTIBODY POSITIVE MYASTHENIA GRAVIS: A U.S. EXPERIENCE

We performed a retrospective chart review on 53 muscle‐specific kinase antibody (MuSK‐Ab)‐positive myasthenia gravis (MG) patients at nine university‐based centers in the U.S. Of these, 66% were Caucasian, 85% were women, and age of onset was 9–79 years. Twenty‐seven patients were nonresponsive to anticholinesterase therapy. Myasthenia Gravis Foundation of America improvement status was achieved in 53% patients on corticosteroids, 51% with plasma exchange, and in 20% on intravenous immunoglobulin (IVIG). Thymectomy was beneficial in 7/18 patients at 3 years. Long‐term (≥3 years) outcome was very favorable in 58% of patients who achieved remission and/or minimal manifestation status. Overall, 73% improved. There was one MG‐related death. This survey reinforces several cardinal features of MuSK‐Ab‐positive MG, including prominent bulbar involvement and anticholinesterase nonresponsiveness. Facial or tongue atrophy was rare. Most patients respond favorably to immunotherapy. The best clinical response was to corticosteroids and plasma exchange, and the poorest response was to IVIG. Long‐term outcome is favorable in about 60% of cases. Muscle Nerve, 2009

Epidemiologic evidence for a changing natural history of myasthenia gravis

Objective: To survey the epidemiologic literature for evidence of an increasing prevalence of myasthenia gravis (MG) over time, and to explore the reasons for the increase. Data Sources: We found population-based reports of the epidemiology of MG by searching bibliographic databases. We used MG, epidemiology, prevalence, incidence, and mortality as search terms. Study Selection: We included population-based studies that reported the number of cases and the time period from which rates were calculated. Statistical Methods: We performed a regression analysis of rates versus date of study, comparing the slopes of regression lines for prevalence, incidence, and mortality. We performed a second analysis grouping rates by decade of study and calculating a mean rate weighted by the size of the population studied. We calculated 95% confidence intervals for each rate. Results: We included 33 studies from 1950 through 1995. Prevalence and incidence rates increased over time, but the regression line for prevalence significantly exceeded that for incidence. Mortality rates declined slightly. The weighted means for prevalence rose significantly, but there was no significant change in incidence or mortality. Conclusion: The prevalence of MG has increased over the past forty-five years, probably because patients with the disease have longer life spans owing to present-day treatment. NEUROLOGY 1996;47: 1233-1238

Lumbosacral spinal evoked potentials in humans

Evoked potentials in response to submaximal electrical stimuli to the peroneal or tibial nerves were recorded from the lumbosacral region in 18 normal subjects. Averaging of 128 responses from recording electrodes over spinous processes S1 to T11, with a reference electrode on the contralateral iliac crest, demonstrated potentials of 0.5 to 1.8 μV, with two well-defined negative peaks having latencies proportional to the distance between the stimulating and recording electrodes. The first peak originated from a traveling wave of depolarization in afferent fibers in the cauda equina, and the second peak originated in the spinal cord. F waves, H reflexes, microreflexes, and volume-conducted muscle responses did not contribute to these potentials.

Creatine monohydrate in ALS: Effects on strength, fatigue, respiratory status and ALSFRS

Our objective was to determine the effect of creatine monohydrate on disease progression in patients with amyotrophic lateral sclerosis (ALS). One hundred and seven patients with the diagnosis of probable or definite ALS, of less than five years duration from symptom onset, were randomized to either treatment with daily creatine monohydrate (5 g/d) or placebo. In this multicenter, double-blinded study we followed changes in disease progression: using quantitative measures of strength via maximal isometric voluntary contraction, forced vital capacity, ALSFRS, quality of life, fatigue and survival. Patients were followed for nine months. The results showed that creatine monohydrate did not significantly improve motor, respiratory or functional capacity in this patient population. The drug was well tolerated and the study groups well balanced, especially considering the absence of forced vital capacity criteria for entrance into the study. There was a trend toward improved survival in patients taking daily creatine monohydrate and this was identical to the trend seen in another recently published report of creatine in ALS patients 1. In conclusion, creatine monohydrate (5 g/d) did not have an obvious benefit on the multiple markers of disease progression measured over nine months. We measured fatigue during isometric contraction and found no significant improvement despite anecdotal patient reports prior to and during the study. The trend toward improved survival was also found in another recently completed blinded trial using creatine monohydrate. Further investigation on the possible survival benefit of creatine in this patient population is ongoing.

R(+) pramipexole as a mitochondrially focused neuroprotectant: Initial early phase studies in ALS

R(+) pramipexole (PPX) is a lipophilic cation that concentrates into brain and mitochondria and efficiently scavenges reactive oxygen and nitrogen species (RONS). Under the auspices of a Physician‐Sponsor IND, R(+)PPX was dosed to small numbers of ALS patients for tolerability and safety while efficacy measures were also collected. The purpose of this paper is to describe the outcomes of these initial clinical studies. In a futility design study, 30 patients with early SALS were evaluated monthly for ALSFRS‐R scores and FVC measurements for three months during lead‐in, followed by open‐label dosing at 30 mg/day of R(+)PPX for the next six months. In the dose escalation study, 10 subjects with early ALS received daily doses of R(+)PPX from 10 mg t.i.d. to 100 mg t.i.d. over seven weeks. In the open‐label extension analysis, subjects from the initial studies were treated with 30 mg/day for at least six months, then switched to 60 mg/day. R(+)PPX was tolerated well in all studies. In the futility study, slopes of decline in ALSFRS‐R scores and neurophysiological index (NI) values yielded non‐significant reductions during treatment. In the dose‐escalation study, all subjects increased daily R(+)PPX intake safely to 100 mg t.i.d. Markers of ALS did not change (ALSFRS‐R) or improved (FVC). Trough and peak plasma (PPX) increased linearly with dosing, and several subjects achieved plasma (PPX) >1 µM. In the open‐label extension protocol, changing from 30 to 60 mg/day caused a non‐significant 17% reduction in slope of decline of ALSFRS‐R. It was concluded that R(+)PPX was tolerated well in long‐term dosing at 30 and 60 mg/day. Encouraging but non‐significant effects of R(+)PPX on ALS decline were observed. High doses of R(+)PPX were tolerated well and yielded neuroprotective plasma levels. These findings support longer‐term testing of higher R(+)PPX doses as a potential disease‐altering therapy for SALS.

Hereditary motor-sensory neuropathy(HMSN): Possible X-linked dominant inheritance

The inheritance of the hereditary motor and sensory neuropathies (HMSN) is usually autosomal dominant. We studied a kinship with a pattern of X-linked dominant inheritance. The phenotype was similar to HMSN of the “intermediate” type. Men were more severely affected than women, and hypertrophic nerves were not found. Nerve conduction was very slow in men, but it was mildly slow or normal in women. No male-to-male transmission was found in six generations.