Randomized trial of oral versus enteral feeding for patients with postoperative pancreatic fistula after pancreatoduodenectomy.

BACKGROUND: Whether continued oral feeding may have a negative impact on healing of postoperative pancreatic fistula (POPF) is unclear. The aim was to test the hypothesis that oral feeding is non-inferior to enteral feeding in closure of POPF after pancreatoduodenectomy, and to clarify the effects of oral feeding on the duration and grade of POPF. METHODS: This multicentre, non-inferiority randomized trial of oral or enteral feeding of patients with POPF after pancreatoduodenectomy recruited patients between August 2013 and September 2016. The primary efficacy outcome was the 30-day fistula closure rate. The prespecified non-inferiority margin was 15 per cent. Other efficacy outcomes included grade of fistula, and hospital stay and costs. RESULTS: A total of 114 patients were included, and received oral (57) or enteral (57) feeding. The two groups were balanced in baseline characteristics and no patient was lost to follow-up. In intention-to-treat analysis, oral feeding was non-inferior to enteral feeding in terms of 30-day fistula closure rate (88 versus 89 per cent respectively; difference -1·8 per cent, lower limit of 95 per cent c.i. -14·4 per cent; P = 0·020 for non-inferiority). Compared with enteral feeding, oral feeding significantly reduced hospital costs and duration of stay. No significant differences were noted in the number of patients whose POPF evolved into grade B/C, or other outcomes. CONCLUSION: Oral feeding in patients with POPF after pancreatoduodenectomy did not increase the duration or grade of POPF, and was associated with reduced duration of stay and hospital costs. Registration number: NCT01755260 (http://www.clinicaltrials.gov).

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety.

BACKGROUND: The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy. PATIENTS AND METHODS: This analysis evaluated pooled data from two phase I trials [NCT00516373 (study 2); NCT00777582 (study 24)] and four phase II trials [NCT00494442 (study 9); NCT00628251 (study 12); NCT00679783 (study 20); NCT01078662 (study 42)] that recruited women with relapsed ovarian, fallopian tube or peritoneal cancer. All patients had a documented gBRCAm and were receiving olaparib 400 mg monotherapy twice daily (capsule formulation) at the time of relapse. Objective response rate (ORR) and duration of response (DoR) were evaluated using original patient outcomes data for patients with measurable disease at baseline. RESULTS: Of the 300 patients in the pooled population, 273 had measurable disease at baseline, of whom 205 (75%) had received ≥3 lines of prior chemotherapy. In the pooled population, the ORR was 36% [95% confidence interval (CI) 30-42] and the median DoR was 7.4 months (95% CI 5.7-9.1). The ORR among patients who had received ≥3 lines of prior chemotherapy was 31% (95% CI 25-38), with a DoR of 7.8 months (95% CI 5.6-9.5). The safety profile of olaparib was similar in patients who had received ≥3 lines of prior chemotherapy compared with the pooled population; grade ≥3 adverse events were reported in 54% and 50% of patients, respectively. CONCLUSION: Durable responses to olaparib were observed in patients with relapsed gBRCAm ovarian cancer who had received ≥3 lines of prior chemotherapy. CLINICALTRIALSGOV: NCT00516373; NCT00494442; NCT00628251; NCT00679783; NCT00777582; NCT01078662.

Long-term safety and efficacy of preladenant in subjects with fluctuating Parkinson's disease.

BACKGROUND: Preladenant is a selective adenosine A2A receptor antagonist under investigation for Parkinson's disease treatment. METHODS: A phase 2 36-week open-label follow-up of a double-blind study using preladenant 5 mg twice a day as a levodopa adjunct in 140 subjects with fluctuating Parkinson's disease was conducted. The primary end point was adverse event (AE) assessment. Secondary (efficacy) analyses included hours/day spent in OFF and ON states and dyskinesia prevalence/severity. RESULTS: The 36-week open-label phase was completed by 106 of 140 subjects (76%). AE-related treatment discontinuations occurred in 19 subjects (14%). Treatment-emergent AEs, reported by ≥15% of subjects, were dyskinesia (33%) and constipation (19%). Preladenant 5 mg twice a day provided OFF time reductions (1.4-1.9 hours/day) and ON time increases (1.2-1.5 hours/day) throughout the 36-week treatment relative to the baseline of the double-blind study. CONCLUSIONS: Long-term preladenant treatment (5 mg twice a day) was generally well tolerated and provided sustained OFF time reductions and ON time increases.

Age effects on placebo response rates in clinical trials of acute agents for migraine: pooled analysis of rizatriptan trials in adults.

This study examined the effect of age on placebo response rates in rizatriptan trials in adults. Data from eight rizatriptan adult trials involving patients treating moderate/severe migraine attacks with rizatriptan 5 mg (N = 1819), rizatriptan 10 mg (N = 2046) or placebo (N = 1322) were pooled for post hoc analysis. Logistic regression was used to model 2-h pain relief (reduction to mild or none) and 2-h pain freedom rates by treatment groups. Older patients had lower placebo response rates than younger patients; the estimated odds ratio (older vs. younger) for a 10-year age increase was 0.83 for pain relief [95% confidence interval (CI) 0.75, 0.93] and 0.81 for pain freedom (95% CI 0.68, 0.97). The response proportion vs. age trend was flat for rizatriptan 5 mg and slightly increased for rizatriptan 10 mg. The treatment-by-age interaction was significant for pain relief (P < 0.001) and pain freedom (P = 0.001), suggesting an increasing trend of treatment advantage of rizatriptan over placebo as age increased. Age appeared to be an important predictor of placebo response rate in rizatriptan trials, with older patients being less likely to respond to placebo and more likely to respond to rizatriptan.

Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling.

Endometrial cancer is the third most common gynecologic malignancy and the ninth most common malignancy for females overall in Hong Kong. Approximately 80% or more of these cancers are endometrioid endometrial adenocarcinomas. The aim of this study was to reveal genes contributing to the development of endometrioid endometrial cancer, which may impact diagnosis, prognosis and treatment of the disease. Whole-genome gene expression analysis was completed for a set of 55 microdissected sporadic endometrioid endometrial adenocarcinomas and 29 microdissected normal endometrium specimens using the Affymetrix Human U133 Plus 2.0 oligonucleotide microarray. Selected genes of interest were validated by quantitative real-time-polymerase chain reaction (qRT-PCR). Pathway analysis was performed to reveal gene interactions involved in endometrial tumorigenesis. Unsupervised hierarchical clustering displayed a distinct separation between the endometrioid adenocarcinomas and normal endometrium samples. Supervised analysis identified 117 highly differentially regulated genes (>or=4.0-fold change), which distinguished the endometrial cancer specimens from normal endometrium. Twelve novel genes including DKK4, ZIC1, KIF1A, SAA2, LOC16378, ALPP2, CCL20, CXCL5, BST2, OLFM1, KLRC1 and MBC45780 were deregulated in the endometrial cancer, and further validated in an independent set of 56 cancer and 29 normal samples using qRT-PCR. In addition, 10 genes were differentially regulated in late-stage cancer, as compared to early-stage disease, and may be involved in tumor progression. Pathway analysis of the expression data from this tumor revealed an interconnected network consisting of 21 aberrantly regulated genes involved in angiogenesis, cell proliferation and chromosomal instability. The results of this study highlight the molecular features of endometrioid endometrial cancer and provide insight into the events underlying the development and progression of endometrioid endometrial cancer.

Onset of feedback reactions underlying vertebrate rod photoreceptor light adaptation.

Light adaptation in vertebrate photoreceptors is thought to be mediated through a number of biochemical feedback reactions that reduce the sensitivity of the photoreceptor and accelerate the kinetics of the photoresponse. Ca2+ plays a major role in this process by regulating several components of the phototransduction cascade. Guanylate cyclase and rhodopsin kinase are suggested to be the major sites regulated by Ca2+. Recently, it was proposed that cGMP may be another messenger of light adaptation since it is able to regulate the rate of transducin GTPase and thus the lifetime of activated cGMP phosphodiesterase. Here we report measurements of the rates at which the changes in Ca2+ and cGMP are followed by the changes in the rates of corresponding enzymatic reactions in frog rod outer segments. Our data indicate that there is a temporal hierarchy among reactions that underlie light adaptation. Guanylate cyclase activity and rhodopsin phosphorylation respond to changes in Ca2+ very rapidly, on a subsecond time scale. This enables them to accelerate the falling phase of the flash response and to modulate flash sensitivity during continuous illumination. To the contrary, the acceleration of transducin GTPase, even after significant reduction in cGMP, occurs over several tens of seconds. It is substantially delayed by the slow dissociation of cGMP from the noncatalytic sites for cGMP binding located on cGMP phosphodiesterase. Therefore, cGMP-dependent regulation of transducin GTPase is likely to occur only during prolonged bright illumination.

Prolactin (PRL) processing by kallikrein: production of the 21-23.5K PRL-like molecules and inferences about PRL storage in mature secretory granules.

We have previously described a series of C-terminally-clipped forms of PRL, the 21-23.5K PRL-like molecules (PLMs). Because we noted estrogen (E2) induction of PLMs and E2 also induces a pituitary glandular kallikrein, we have investigated the possibility that processing of PRL by kallikrein is responsible for the production of the PLMs. Subcellular fractionation of pituitaries from control or E2-treated female rats showed total kallikrein to be concentrated 1- to 4-fold and 6- to 20-fold in the granules (vs. original homogenate) from control and E2-treated animals, respectively. Cleavage of purified PRL by kallikrein resulted in the formation of large quantities of a number of the PLMs. Incubation of secretory granules derived from control or E2-treated animals under the same conditions showed no cleavage of PRL in the absence of a limiting granule membrane and a small production of the PLMs in the presence of a granule membrane. Production in the latter instance was slightly greater in granules derived from E2-treated animals. Addition of purified kallikrein to secretory granules from control or E2-treated animals in the presence or absence of granule membranes, resulted in the additional production of large amounts of only the smallest PLM (PLM 9), indicating a lack of cleavage of the two most C-terminal sites for the enzyme. Increasing the concentration of beta-mercaptoethanol to 0.64 M, to ensure monomerization of the granule PRL, had no effect on endogenous kallikrein activity of the number of products resulting from the addition of exogenous kallikrein to granules. In summary: 1) purified kallikrein can cleave purified PRL to form products which run with the same isoelectric point and mol wt values as the PLMs; 2) kallikrein is present in PRL secretory granules; 3) some PLM production occurs in a membrane-bound secretory granule fraction, but none occurs after removal of the membrane; this intragranular production, like cleavage of purified PRL with purified kallikrein, is dependent on the presence of a detergent and a reducing agent; 4) cleavage of granular PRL by exogenous kallikrein is limited to a single site and the more C-terminal sites are protected; and 5) protection of the C-terminus is not removed by intermolecular and intramolecular disulfide bond reduction. We conclude: 1) that pituitary glandular kallikrein is a strong candidate for the enzyme responsible for the production of the PLMs, and 2) that there is some element of PRL storage, other than intermolecular disulfide bonds, which involves the C-terminus of the molecule.

Biosynthesis of the secreted 24 K isoforms of prolactin.

PRL exists within the mammotroph population in a number of different molecular forms. Several of these forms are best described as isoforms, as they have the same mol wt (24 K), but differ in their net charges. In this study we have used in vitro translation assays to ascertain the number of 24 K translation products of normal pituitary messenger RNA (mRNA), and, finding only one, have used both in vitro translation assays and subcellular fractionation to determine the intracellular site of the posttranslational modification of this single translation product. Translation of mRNA from normal pituitary tissue or GH3 cells resulted in the apparent production of a number of pre-PRLs, but in only a single rough microsome-processed form of PRL, 24 K isoform 2. Longer term translation assays utilizing a variety of isotopes failed to show any evidence for rough microsomal posttranslational modification of isoform 2. Subcellular fractionation, using a discontinuous sucrose gradient, however, produced a membrane-bound large secretory granule fraction which, when isolated, contained essentially only isoform 2, and which had the capacity to convert isoform 2 to isoforms 3 and 3' by posttranslational phosphorylation.

Mammotroph autoregulation: the differential roles of the 24K isoforms of prolactin.

In this study we have attempted to determine which of the secreted 24K isoforms was responsible for autocrine regulation of PRL secretion by comparing the isoforms synthesized and secreted by normal cells, which do autoregulate, with those synthesized and secreted by GH3 cells, which do not normally autoregulate. Comparable numbers of cells were washed free of serum and then extracted into Tris-buffered saline by sonication and detergent treatment. Proteins present in these cell extracts and in samples of culture medium were then precipitated with cold acetone (-20 C; 48 h) and subsequently dissolved in urea-lysis buffer for 2-dimensional (2-D) electrophoresis. The 2-D patterns for normal cells showed four 24K PRL isoforms inside the cells and three 24K PRL isoforms (designated 2, 3, and 3') secreted into the medium. The 2-D patterns for GH3 cells showed very little intracellular storage of PRL, but what was present was identified as 24K PRL isoform 2. The GH3 cells secreted large amounts of only 24K PRL isoform 2. Preparations of PRL containing only isoforms 1,2, and 3 (at a total radioimmunoassayable concentration of 5 micrograms/ml PRL) were capable of inducing autoregulation in GH3 cells, as evidence by decreased secretion of prelabeled intracellular PRL. Initiation of autoregulation in GH3 cells caused granulation and the intracellular production of isoform 3. Since a) a preparation containing isoforms 1, 2, and 3 was found to induce autoregulation in GH3 cells, b) isoform 1 is not a secreted form, and c) isoform 2 does not cause autoregulation (at least in GH3 cells), it is deduced that isoform 3 is an autocrine form of PRL. Since initiation of autoregulation in GH3 cells caused those cells to produce isoform 3, it is further deduced that the autoregulatory defect in GH3 cells lies in the actual lack of production of isoform 3 and not in an inherent inability of these cells to produce isoform 3.

Prolactin isoform 2 as an autocrine growth factor for GH3 cells.

Because PRL has growth factor activities in several tissues, we have asked whether it also has autocrine growth factor activity in pituitary GH3 cells. GH3 cells were grown at increasing densities in the presence or absence of antirat PRL (polyclonal and monoclonal) or nonspecific antibodies. Cell proliferation increased with increasing cell density, as did the concentration of PRL in the medium. Antirat PRL, but not control antibody, markedly inhibited but did not eliminate cell proliferation, and this effect was diminished with increasing PRL concentration in the medium. PRL receptors were demonstrated on 40-50% of the cells by indirect immunofluorescence using a specific antirat PRL receptor monoclonal antibody. Cell surface PRL was colocalized to the same 40-50% of the cells and copatched or cocapped along with the receptors. Absence or presence of PRL receptors did not correlate with stage of the cell cycle, as judged by ethidium bromide dual labeling. Cell surface PRL was found to be on PRL-containing cells. These data have fulfilled four criteria necessary for establishment of a substance as a secreted autocrine growth factor: 1) the factor must be secreted; 2) in log growth phase, increased cell proliferation should occur at increased cell densities; 3) the cells must display a receptor for the factor; and 4) there must be a growth response to the factor. Thus we have established that PRL is an autocrine growth factor for at least 40-50% of the GH3 cell population. This, to our knowledge, is the first example of autocrine growth factor activity of a major hormone normotopically expressed.

Patterns of recovery in the Guillain-Barre syndromes.

Clinical, electrodiagnostic, and pathologic studies indicate that the Guillain-Barre syndromes (GBSs) include both primary demyelinating and primary axonal forms. The axonal forms are usually thought to have a poorer prognosis, with less chance for rapid or complete recovery. In northern China, epidemics of one axonal form, acute motor axonal neuropathy (AMAN), occur annually in the summer. Autopsy studies in some fatal cases have demonstrated wallerian-like degeneration of motor roots and motor fibers in the peripheral nerves. Recovery of such patients would require axonal regeneration along the entire length of the nerve fiber. In a 2-year prospective study of GBS at a single hospital in northern China, 42 patients were classified as having either AMAN (32 patients), acute inflammatory demyelinating polyneuropathy (AIDP) (8 patients), or as undetermined (2 patients) by electrodiagnostic criteria. Their recoveries were monitored clinically. The recovery times of AMAN and AIDP patients were similar: the median time to regain the ability to walk 5 meters with assistance was 31 days for patients classified as having AMAN and 32 days for those classified as having AIDP. These rapid recovery times are incompatible with severe wallerian degeneration of the ventral roots and motor nerve fibers. The rapid recoveries observed in AMAN patients could be explained by relatively quickly reversible immune-mediated changes at nodes of Ranvier in motor fibers, by degeneration and regeneration of intramuscular motor nerve terminals, or both.

Physiologic-pathologic correlation in Guillain-Barré syndrome in children.

OBJECTIVE: To correlate electrophysiologic patterns with sural nerve pathology in children with Guillain-Barré syndrome (GBS). BACKGROUND: Based on electrophysiologic and pathologic observations, GBS has been divided into demyelinating and axonal subtypes. The acute motor axonal neuropathy (AMAN) involves predominantly motor nerve fibers with a physiologic pattern suggesting axonal damage, whereas the acute inflammatory demyelinating polyneuropathy (AIDP) involves both motor and sensory nerve fibers with a physiologic pattern suggesting demyelination. In this study, we sought to confirm these observations by correlating sural nerve pathology with electrophysiologic findings in GBS patients. METHODS: Biopsies of sural nerve from 29 of 50 prospectively studied GBS patients were obtained. Nerves were examined by light and electron microscopy, and with immunocytochemistry for macrophages, lymphocytes, and complement activation products. RESULTS: Sural nerves from AMAN patients were normal or had only a few (0.1% to 0.7%) degenerating fibers without lymphocytic infiltration or complement activation. One patient with reduced sural sensory nerve action potential classified as acute motor sensory axonal neuropathy (AMSAN) had many degenerating fibers (2.3%) in the sural nerve. All three AIDP patients displayed active demyelination, and in two patients, lymphocytic infiltration and complement activation products were observed on the abaxonal Schwann cell surface. CONCLUSION: Classification of Guillain-Barré syndrome subtypes based on motor conduction studies correlates closely with pathologic changes seen in sural nerve. In acute motor axonal neuropathy cases, the sural nerve is almost completely spared pathologically. In acute inflammatory demyelinating polyneuropathy cases, macrophage-mediated demyelination and lymphocytic infiltration are common in the biopsies of sural nerves.

Motor nerve terminal degeneration provides a potential mechanism for rapid recovery in acute motor axonal neuropathy after Campylobacter infection.

We investigated the possible mechanisms of paralysis and recovery in a patient with the acute motor axonal neuropathy (AMAN) pattern of the Guillain-Barré syndrome. The AMAN pattern of GBS is characterized clinically by acute paralysis without sensory involvement and electrodiagnostically by low compound motor action potential amplitudes, suggesting axonal damage, without evidence of demyelination. Many AMAN patients have serologic or culture evidence of recent Campylobacter jejuni infection. Pathologically, the most severe cases are characterized by wallerian-like degeneration of motor axons affecting the ventral roots as well as peripheral nerves, but some fatal cases have only minor changes in the roots and peripheral nerves, and some paralyzed patients with the characteristic electrodiagnostic findings of AMAN recover rapidly. The mechanism of paralysis and recovery in such cases has been uncertain. A 64-year-old woman with culture-proven Campylobacter upsaliensis diarrhea developed typical features of AMAN. She improved quickly following plasmapheresis. Her serum contained IgG anti-GM1 antibodies. The lipopolysaccharide of the organism bound peanut agglutinin. This binding was blocked by cholera toxin, suggesting that the organism contained the Gal(beta1-3)GalNAc epitope of GM1 in its lipopolysaccharide. Motor-point biopsy showed denervated neuromuscular junctions and reduced fiber numbers in intramuscular nerves. In contrast, the sural nerve biopsy was normal and skin biopsy showed normal dermal and epidermal innervation. In AMAN the paralysis may reflect degeneration of motor nerve terminals and intramuscular axons. In addition, the anti-GM1 antibodies, which can bind at nodes of Ranvier, might produce failure of conduction. These processes are potentially reversible and likely to underlie the capacity for rapid recovery that characterizes some cases of AMAN.

Campylobacter jejuni lipopolysaccharides in Guillain-Barré syndrome: molecular mimicry and host susceptibility.

OBJECTIVE: This study was designed to determine if the presence of specific ganglioside-like moieties in Campylobacter lipopolysaccharides (LPSs) is related to the development of Guillain-Barré syndrome (GBS), and to discover how frequently such moieties, including GM1, are present in these LPSs. METHODS: We studied Campylobacter isolates and sera from seven patients with GBS (five acute motor axonal neuropathy, one acute inflammatory demyelinating polyneuropathy, and one Fisher's syndrome), and compared them with similar specimens from patients with Campylobacter enteritis alone. RESULTS: All GBS patients had antiganglioside antibodies. Anti-GM1 and anti-GD1a titers were significantly elevated in post-Campylobacter GBS, both axonal and demyelinating, compared with normal control subjects or those with uncomplicated Campylobacter diarrhea. Campylobacter isolated from patients with GBS and with enteritis alone had similar ganglioside-like moieties. CONCLUSIONS: These results indicate that patients who develop GBS respond differently to the ganglioside-like epitopes on Campylobacter than do non-GBS diarrhea patients. Our findings support a role for host susceptibility as a determinant for the outcome following Campylobacter infection. These findings have important implications for the development of vaccines against Campylobacter jejuni.

Production and secretion of the 21-23.5 kDa prolactin-like molecules.

We recently described the presence of a series of prolactin (PRL)-like molecules (PLMs) in the rat pituitary gland and showed that their formation was not due to artifactual proteolysis of 24 kDa PRL during extraction or to degradation of PRL in lysosomes. In this study we have found (1) in vitro translation of pituitary cell RNA to result in the production of only 24 kDa monomer isoform 2 and no PLMs, (2) that secretion of newly synthesized PLMs is differently regulated than at least a proportion of newly synthesized monomers, (3) that secretion of newly synthesized PLMs occurs after at least a 6 h delay, (4) that cysteamine (a) inhibits the release of the PLMs, (b) causes an increase in their amount versus isoform 2, and (c) causes an intracellular accumulation of pleiomorphic, immature secretory granules, and (5) that cells grown under degranulating culture conditions do not contain PLMs. These results, using normal anterior pituitary cells in primary culture, demonstrate the potential for differential release of the PLMs versus monomer PRL in vivo and are consistent with the production of the PLMs from 24 kDa monomer isoform 2 during secretory granule condensation.

Molecular mimicry in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is the commonest cause of acute flaccid paralysis worldwide. Recent pathological and electrodiagnostic studies indicated that there are different patterns within this syndrome. The demyelinating pattern predominates in North America and Europe, whereas axonal variants of GBS occur more frequently in Northern China. Infection with Campylobacter jejuni is one of the most frequently recognized antecedent events in all variants of GBS. The lipopolysaccharides of these organisms share ganglioside-like epitopes with peripheral nerves, and patients with GBS have antiganglioside antibodies. These observations have given rise to the hypothesis that "molecular mimicry" is the immunopathogenic mechanism of injury to peripheral nerve fibers. With this hypothesis in view, we summarize our experience of GBS as it occurs in Northern China. To explore the role of molecular mimicry in this cohort we sought evidence of preceding Campylobacter infection and correlated this with clinical characteristics and antiganglioside serology. Based on our results we propose a sequence of pathogenic events leading to peripheral nerve injury in GBS.

Clinical correlates and prognosis in early spindle coma.

OBJECTIVE: To determine the prognostic significance of spindle coma (SC) according to etiology and EEG reactivity. METHODS: We reviewed 15 patients with SC due to various causes within 8 days of coma to determine the prognostic significance of this EEG pattern. RESULTS: The outcome among survivors was favorable: among 13 survivors, 9 were independent in all activities of daily living (ADLs) at 6 months; 3 were dependent in all ADLs; and one remained in coma. EEG reactivity to noxious stimuli best predicted outcome: All patients (whatever the coma etiology) with EEG reactivity survived; conversely, not all patients without EEG reactivity died. CONCLUSION: In our patients, EEG reactivity independent of etiology predicted survival, neurological examination did not predict outcome. Most SC survivors had a meaningful recovery achieving all ADLs. From the literature, the cause of SC was predictive of outcome: encephalopathy, seizures and trauma had the best prognosis while hypoxia, CRA and structural lesions carried the worst. Literature review revealed that 23% of patients [56/242] died or remained in a persistent vegetative state (PVS). Best outcomes occurred when SC was due to drugs, encephalopathy or seizures: (0/14 died or were in a PVS). With trauma 15% [25/169] died or were in a PVS). Intermediate outcomes occurred with hypoxia and cardio-respiratory arrest (CRA): 33% [7/21] died or were in a PVS. The gravest outcomes occurred with brain-stem and cerebral infarctions, and tumors: 73% [22/30] died or were in a PVS.

Etiology, neurologic correlations, and prognosis in alpha coma.

OBJECTIVE: To determine the factors affecting prognosis in alpha coma (AC). METHODS: Retrospective review of 36 study patients, 36 control coma patients matched for age and etiology, and meta-analysis of 335 cases in the world literature. RESULTS: Principal causes were cardiorespiratory arrest (CRA) (21 patients); infection, metabolic dysfunction, head trauma (3 each); and drugs, stroke and hypoxia (2 each). Outcome was predicated by EEG reactivity to noxious stimuli. Fourteen of the 15 patients with reactive EEGs, had measurable outcome, 8 awoke - all but two had etiologies other than CRA. Fourteen of 19 patients without EEG reactivity died; two had support discontinued and 3 awoke. Following CRA, 16/21 patients died and 3 had support discontinued. Only 3 patients made a good recovery - all with toxic or metabolic etiologies. Literature meta-analysis of 335 cases showed that overall, AC carried a poor prognosis (76% died). CRA (226 cases) had an 88% mortality; strokes (29 cases), a 90% mortality; hypoxia without cardiac arrest (28 cases), a 61% mortality; drug-induced AC (25 cases), an 8% mortality. CONCLUSIONS: Although the cause of AC largely predicts outcome, EEG reactivity in AC predicted survival: most patients with reactivity awoke; most of those without, died. Few survivors had meaningful recovery.