Cushing's Ulcer Research Articles

Treatment of a Cushing's ulcer in a 7-y.o. child after a tumor (medulloblastoma) removal in ventricle IV

BACKGROUND: Cushing's ulcer is a stress ulcer in the stomach or duodenum which basic etiological factor is increased intracranial pressure. The increased intracranial pressure is caused, most often, by intracranial neoplasms, cranial-cerebral injury or previous neurosurgical interventions. Cushing's ulcers are usually solitary and deep, often complicated with recurrent gastrointestinal bleedings and less often with perforations. In cases of suspected perforation in a complex anatomical localization (posterior wall of the duodenum), the method of choice according to the world literature is computed tomography with intravenous contrast. Subsequently, after brief preoperative preparation, indications for laparoscopy or laparotomy with subsequent ulcer closure are determined. In the absence of free gas in the abdominal cavity, the "gold standard" for diagnosis and treatment is esophagogastroduodenoscopy. During esophagogastroduodenoscopy, it is necessary to visualize the source of gastrointestinal bleeding and determine if it is ongoing. In cases of ongoing gastrointestinal bleeding, endoscopic hemostasis is performed. If it is not possible to establish the source of bleeding and/or if local hemostasis attempts are unsuccessful, endovascular arterial embolization is recommended. If all minimally invasive methods are ineffective, radical methods such as laparoscopy or laparotomy with visualization of the source of bleeding, cessation of bleeding, and ulcer closure are employed. Clinical Case Description. This clinical case demonstrates the severity and unpredictability of the clinical course of Cushing's ulcer complicated by gastrointestinal bleeding. The patient underwent multiple hemostatic procedures through esophagogastroduodenoscopy and arterial embolization. However, despite all minimally invasive treatment methods, the patient's condition required radical surgical treatment. CONCLUSION: There is no information in the world literature about the algorithm for managing recurrent gastrointestinal bleeding in the context of Cushing's ulcer. The authors recommend to covert to more radical treatment only after all minimally invasive techniques turned to be ineffective.

A Reappraisal of the Pathophysiology of Cushing Ulcer: A Narrative Review.

In 1932, Harvey Cushing described peptic ulceration secondary to raised intracranial pressure and attributed this to vagal overactivity, causing excess gastric acid secretion. Cushing ulcer remains a cause of morbidity in patients, albeit one that is preventable. This narrative review evaluates the evidence pertaining to the pathophysiology of neurogenic peptic ulceration. Review of the literature suggests that the pathophysiology of Cushing ulcer may extend beyond vagal mechanisms for several reasons: (1) clinical and experimental studies have shown only a modest increase in gastric acid secretion in head-injured patients; (2) increased vagal tone is found in only a minority of cases of intracranial hypertension, most of which are related to catastrophic, nonsurvivable brain injury; (3) direct stimulation of the vagus nerve does not cause peptic ulceration, and; (4) Cushing ulcer can occur after acute ischemic stroke, but only a minority of strokes are associated with raised intracranial pressure and/or increased vagal tone. The 2005 Nobel Prize in Medicine honored the discovery that bacteria play key roles in the pathogenesis of peptic ulcer disease. Brain injury results in widespread changes in the gut microbiome in addition to gastrointestinal inflammation, including systemic upregulation of proinflammatory cytokines. Alternations in the gut microbiome in patients with severe traumatic brain injury include colonization with commensal flora associated with peptic ulceration. The brain-gut-microbiome axis integrates the central nervous system, the enteric nervous system, and the immune system. Following the review of the literature, we propose a novel hypothesis that neurogenic peptic ulcer may be associated with alterations in the gut microbiome, resulting in gastrointestinal inflammation leading to ulceration.

Thrombin action on NST astrocytes disrupts glycemic and respiratory control

Burns and severe trauma can produce a post‐injury “metabolic self‐destruction” characterized by catabolic metabolism and hyperglycemia. The severity of the hyperglycemia is highly correlated with post‐trauma morbidity and mortality. No mechanism has been posited to connect severe trauma with a loss of autonomic control over metabolism. However, traumatic injury causes other failures of autonomic function; one of those, gastric stasis and ulceration (“Cushing's Ulcer”) has recently been connected with the generation of thrombin. As a protease, thrombin (produced as a consequence of tissue injury) acts on G‐protein‐coupled protease‐activated receptors (PAR). Our previous work established that PAR1 receptors located on astrocytes in the autonomically critical nucleus of the solitary tract (NST) are responsible for modulating gastric control circuit neurons. The NST is at the center of a homeostatic control nexus that receives vast quantities of visceral afferent data from cranial nerve afferents including the vagus. This region of the hindbrain is also outside the “blood‐brain barrier” and is accessible to large molecules from the circulation. The NST uses this neural and chemical information to regulate gastrointestinal, metabolic, cardiorespiratory, endocrine, and behavioral functions. Astrocytes in the hindbrain have been also been implicated as important detectors of low glucose or glucose utilization and when activated, these astrocytes trigger CRR. There may be a convergence between the effects of thrombin to derange hindbrain gastrointestinal control and the hindbrain circuitry that initiates counter‐regulatory responses (CRR) to increase glycemia in reaction to critical hypoglycemia. We tested the hypothesis that administration of thrombin to the floor of the fourth ventricle (4V) or directly into the NST could trigger increases in glycemia through the mediation of astrocytes. Pre‐exposure of the 4V to fluorocitrate (FC; a selective blocker of astrocyte metabotropic signaling) was used to evaluate astrocyte involvement in thrombin‐triggered changes in glycemia. Our results suggest that thrombin acts within the NST to increase glycemia through an astrocyte dependent mechanism. Blockade of purinergic, but not glutamatergic, gliotransmission pathways interrupted the effect of thrombin to increase glycemia. Our studies also revealed that thrombin, acting in the NST, produces a rapid, dramatic and potentially lethal suppression of respiratory rhythm that was also a function of purinergic gliotransmission. These results suggest that the critical connection between traumatic injury and a general collapse of autonomic regulation involves thrombin action on astrocytes.Support or Funding InformationNIH NIDDK 108765, NIH NINDS 96113This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A Judical Autopsy Case of a Craniopharyngioma Patient Who Experienced Three Times Local Recurrences and Died on the Forth Postoperative Days

In this case, a 70-year-old male craniopharyngioma patient experienced three times to local recurrences. On the forth postoperative days after the fourth surgery, the patient died of acute renal failure and decreased blood pressure. The judicial autopsy, conducted 15 hours later, found multiple small bleeding ulcers in the gaster, and a large amount of blood had filled in the gaster and small intestine. The cause of death was considered to be respiratory failure due to congestive edema seen in the lungs, and hemorrhagic shock due to multiple gastric ulcers (Cushing ulcer).

Cushing's ulcer: Further reflections.

Background:Brain tumors, traumatic head injury, and other intracranial processes including infections, can cause increased intracranial pressure and lead to overstimulation of the vagus nerve. As a result, increased secretion of gastric acid may occur which leads to gastro-duodenal ulcer formation known as Cushing's ulcer.Methods:A review of original records of Dr. Harvey Cushing's patients suffering from gastro-duodenal ulcers was performed followed by a discussion of the available literature. We also reviewed the clinical records of the patients never reported by Cushing to gain his perspective in describing this phenomenon. Dr. Cushing was intrigued to investigate gastro-duodenal ulcers as he lost patients to acute gastrointestinal perforations following successful brain tumor operations. It is indeed ironic that Harvey Cushing developed a gastro-duodenal ulcer in his later years with failing health.Results:Clinically shown by Cushing's Yale Registry, a tumor or lesion can disrupt this circuitry, leading to gastroduodenal ulceration. Cushing said that it was “reasonable to believe that the perforations following posterior fossa cerebellar operations were produced in like fashion by an irritative disturbance either of fiber tracts or vagal centers in the brain stem.”Conclusion:Harvey Cushing's pioneering work depicted in his Yale registry serves as a milestone for continuing research that can further discern this pathway.

Severe Erosive Hemorrhagic Gastritis in a Pediatric Patient

An 11-year-old-Hispanic boy with relapsed acute lymphocytic leukemia presented with hematemesis and melena 1 week after admission for sepsis and rhabdomyolysis. He had presyncope and presented to an outside hospital with hemoglobin 8.4 mg/dL. His recent chemotherapeutic experimental protocol included epratuzumab, vincristine, PEG-asparaginase, prednisone, and intrathecal methotrexate. He denied NSAID use and was on ranitidine prophylaxis. His physical examination was remarkable for a pale, cushingnoid male with hepatomegaly (14 cm) and without splenomegaly. Rectal examination demonstrated melanotic stool. The balance of the examination was unremarkable. The patient underwent esophagogastroduodenoscopy once he was hemodynamically stable. The gastric mucosa was diffusely ulcerated, with numerous visible vessels. (Fig. 1) Argon plasma coagulation to treat diffuse disease was not available. Bipolar cautery was applied. Initial biopsies showed focal active inflammation and regenerative changes (Fig. 2). Gastrin level was normal and cytomegalovirus, Epstein-Barr virus, herpes simplex virus, adenovirus, Helicobacter pylori testing was negative. Despite a pantoprazole drip, bleeding recurred in a now deep ulcer within the gastric fundus (Fig. 3), which required epinephrine injection, bipolar cautery, and endoscopic clipping. Bleeding subsequently recurred at requiring massive transfusion protocol. Interventional radiology was unsuccessful, achieving hemostasis, and a partial gastric resection with use of factor VIIa was performed. Pathology showed severe ulceration, necrosis, hemorrhage, inflammation, and thrombosis (Fig. 4). No leukemic infiltrate was found. Subsequently, the patient did well.FIGURE 1: Diffuse gastric ulceration of antrum, body, and fundus with numerous visible vessels.FIGURE 2: Mucosal gastric biopsies with focal active inflammation with regenerative changes.FIGURE 3: Actively bleeding ulceration of gastric fundus pre- and posttherapy.FIGURE 4: Full-thickness gastric biopsy with severe ulceration, necrosis, inflammation, thrombosis, and hemorrhage.Severe gastrointestinal bleeding from severe hemorrhagic and erosive gastritis in pediatrics is rarely reported. The cause here is likely multifactorial (1). There are limited pediatric reports on the causes of such severe erosive and hemorrhagic gastritis. This patient did not have an oncologic infiltrate, viral infection, Zollinger-Ellison syndrome, or report NSAID use (2–5). We suspect that the cause was chemotherapeutics and recent sepsis with Cushing ulcer.

Cushing's Ulcer: The Eponym and His Own

One of the least remembered eponyms associated with Harvey Cushing is "Cushing's ulcer." The basis of this credit is a paper published in 1932 in which Cushing describes patients who postoperatively and unexpectedly died of perforated peptic ulcers. It is one of the first descriptions of a stress ulcer and a treatise on the brain-stomach connection. Harvey Cushing was puzzled by the pathogenesis of these peptic ulcerations and perforations and advanced several theories. The least plausible included the bile-vomiting theory suggesting that hemorrhagic ulceration could be produced by a combination of bile and acid in a patient recovering from the anesthetic. Other theories were stimulation of a parasympathetic center in the diencephalon or a disturbance of vagal centers in the brainstem. Quite surprisingly to Cushing, the Boston Herald implicitly insinuated that Cushing found the cause of ulcers and this claim upset him greatly. It is ironic that Harvey Cushing, in his later years with failing health, developed an ulcer himself. Cushing noted in his correspondence that he felt the agitation over this newspaper clipping caused his later ulcer. The first description of a neurogenic ulcer remains an important medical observation and is a testament to Cushing's broad accomplishments.

A Case of Postoperative Herpes Simplex Pneumonia

Herpes simplex virus (HSV) esophagitis is a rare disease and most of cases are reported in the immunocompromised patients2,3,11,15,17,18). We report a case of fatal HSV infection started from herpes labialis and esophagitis. She had initially suffered from perioral ulcer, esophagitis, and interstitial pneumonitis later and eventually died of respiratory insufficiency one month later after the aneurysmal surgery. She did not have any immunocompromised medical history and also had no evidence of herpes encephalitis in laboratory study and magnetic resonance image (MRI). With the availability of effective agents for the treatment of HSV infection, early recognition of HSV esophagitis is important because it may be clinically confused with Cushing ulcer and may be complicated with a fatal pneumonitis.

The legacy of Harvey Cushing.

Dr Harvey Cushing. Illustration by Venita Jay, MD, FRCPC. I is a formidable task for any biographer to record all of the achievements of Harvey William Cushing, commonly known as the Father of American Neurosurgery. Regarded as the leading neurosurgeon of the 20th century, Cushing was a tireless investigator, dedicated teacher, prolific writer, gifted artist, and ardent bibliophile. His name is known to every medical student and is immortalized in the well-known Cushing syndrome, Cushing disease, Cushing reflex, and Cushing ulcer. Cushing also left a lasting legacy in pathology with his work on the pituitary gland and brain tumors. Cushing launched neurosurgery as a distinct discipline and firmly established it as a separate specialty. Every phase of Cushing’s career has been the subject of intense scrutiny, with extensive biographies detailing his college days at Yale, medical training at Harvard, surgical residency at Johns Hopkins, and the years at Peter Bent Brigham and Yale. There are also several well-known biographies of Cushing, including those written by John F. Fulton, Elizabeth H. Thomson, and Justin F. Denzel. Born on April 8, 1869, in Cleveland, Ohio, Cushing was the youngest of 10 children, 7 of whom survived to maturity. His great-grandfather, grandfather, father, and older brother Ned were physicians. Cushing attended Yale College in New Haven, Conn, and graduated from that institution in 1891. While at Yale, Russell Chittenden encouraged in Cushing an interest in physiological chemistry. Cushing greatly admired his father and his brother Ned. He followed in the family tradition and embarked on a medial career, joining Harvard Medical School in Boston, Mass. Cushing attended Harvard from 1891 to 1896 and received his medical degree in 1895. He completed his internship at Massachusetts General Hospital. During his medical school years, Cushing was a keen and observant student, who was able to recognize the importance of new developments. Ether anesthesia had come into vogue, and medical students were called upon to administer it. One patient anesthetized by Cushing died, which disturbed Cushing so much that he wanted to quit medicine. Brooding over the tragedy and hoping that such deaths could be prevented if vital signs were monitored, he embarked on a new venture with fellow student Ernest Amory Codman. Together, they developed a record of an-

Harvey Cushing at the Peter Bent Brigham Hospital.

Harvey Cushing's years at the Peter Bent Brigham Hospital in Boston were marked by the establishment of neurosurgery as a surgical subspecialty. As a clinical neurosurgeon, he performed more than 2000 brain tumor operations in that time and reduced neurosurgical mortality from 50% to only 8%. As a teacher, he trained a whole generation of neurosurgical leaders, created the Society of Neurosurgeons, and indirectly led to the founding of the American Association of Neurological Surgeons. As an author, he produced monographs on pituitary adenomas, acoustic neuromas, meningiomas, gliomas, blood vessel tumors, and tumor surgery and won the Pulitzer Prize for his biography of Sir William Osler. As an investigator, he described Cushing's disease, the Cushing reflex, Cushing's ulcer, the "third circulation" of cerebrospinal fluid, and a variety of other phenomena. And as a book collector, he developed perhaps the most significant collection of antiquarian medical and surgical texts extant. In these Brigham years, he clearly became the Neurosurgeon of the Century.

Cushing's Ulcer as a Consequence of Adrenocorticotropic Hormone Administration for Infantile Spasms

Adrenocorticotropic hormone (ACTH) is the treatment of choice for infantile spasms despite its multiple side effects. This case represents a previously unreported side effect, peptic ulceration, occurring during ACTH treatment of infantile spasms. Two pathophysiologic mechanisms are proposed and examined. A direct effect of ACTH on the duodenum is considered but deemed unlikely. Alternatively, the combination of the patient's communicating hydrocephalus and ACTH's central effects is proposed to have led to increased intracranial pressure and a Cushing's ulcer. The need for pretreatment neuroimaging and H2-receptor antagonist use during ACTH therapy in all cases, along with gastrin level measurements in selected cases, is recommended.

15 - Pathogenesis, Diagnosis and Treatment of Acute Gastric Mucosal Lesions

Stress ulcers are multiple superficial mucosal lesions which occur mainly in the fundus of stomachs of seriously ill patients and should be differentiated from reactivation of a pre-existent ulcer diathesis, Cushing's ulcer following head injury, or drug-induced gastritis. It is generally agreed that luminal acid and pepsin are required for ulceration to develop. Experimental evidence suggests that backdiffusion of acid is closely related to the formation of ulcers. In the absence of overt disruption of the gastric mucosal barrier, ischaemia appears to compromise the ability of the gastric mucosa to dispose of backdiffusing acid, which then results in a decrease in intramural pH and ulceration. Reflux of duodenal contents and diffusion of urea from the blood may contribute to the formation of ulcers. Although endoscopic studies have demonstrated gross mucosal injury within hours of the stressful event in nearly 100 per cent of patients examined, most stress ulcers heal when normal gastric defence mechanisms are restored. However, in a small percentage of patients, stress ulceration may lead to frank gastrointestinal haemorrhage requiring medical and/or surgical intervention. Endoscopic findings in conjunction with the history usually differentiates stress ulcer from other bleeding lesions. Angiography may be used if endoscopy fails to identify the bleeding site. Most episodes of bleeding from stress ulceration resolve on medical management consisting of saline lavage, antacids, and adequate supportive measures. Pharmacoangiography with selective infusion of vasopressin or embolization may be of benefit in selected patients with continued bleeding. Surgery is a last resort and has a predictably high mortality. The operation of choice is controversial, but vagotomy, pyloroplasty and oversewing the ulcers may be a good initial operation. Continued bleeding subsequent to vagotomy and pyloroplasty would require near total gastrectomy. Since results of surgical therapy in established stress ulcer disease are poor, the prevention of bleeding is the most rational approach to the management of this disease. The key to prophylaxis is the maintenance of normal intragastric pH. Antacids appear to be superior to cimetidine in preventing bleeding from stress ulcers, so long as the gastric content is buffered to a pH of 3.5 or greater. In seriously ill patients found in respiratory-surgical intensive care units, hourly titration with antacids is the standard against which other forms of prophylaxis must be rigidly compared.

Stress Ulcers: Their Pathogenesis, Diagnosis, and Treatment

Stress ulcers are multiple, superficial erosions which occur mainly in the fundus and body of the stomach. They develop after shock, sepsis, and trauma and are ofter found in patients with peritonitis and other chronic medical illness. Stress ulcers should be differentiated from reactivation of chronic duodenal or gastric ulcers. Cushing's ulcer following head injury, or drug-induced gastritis. Digestive symptoms are usually absent, hemorrhage is the most common manifestation, and perforation and obstruction are rare. The presence of luminal acid and ischemia are necessary for the production of stress ulcer, while disruption of the gastric mucosal barrier by refluxed duodenal content may contribute to the pathogenesis. Endoscopy is the mainstay of the diagnostic procedure, and angiography should be used if endoscopy fails to identify the bleeding lesions. Medical management should include volume replacement, nasogastric aspiration, and the use of antacid. Selective intraarterial infusion of pitressin has shown encouraging preliminary results. Surgical treatment is reserved only for those patients who continue to bleed despite all medical management. The operation of choice is open to question. We prefer vagotomy, pyloroplasty, and oversewing the ulcers as an initial operation. Since the result of all forms of therapy has been poor, it seems resonable to try to prevent ulcer development. The use of vitamin A, hyperalimentation, and growth hormones is still in an experimental stage. Large clinical studies with case control are necessary before recommendations can be made. The use of potent and frequent antacid to buffer the gastric content has shown promising results; however, these observations need to be confirmed in a properly controlled and randomized study.

Endocrine and gastric secretory changes induced by increased intracranial pressure

A chronic experimental preparation representing an intracranial lesion with increased intracranial pressure is described. Induction of a space-occupying lesion in the right frontoparietal cortical area resulted in hyposecretion of gastric acid and mucus, and an acute duodenal ulcer developed in one of eleven dogs. No evidence of hypothalamic or related structural lesions was noted. Chronic stress was indicated by persistent, marked elevations in plasma cortisol. It is suggested that with decreased renewal of gastric mucus, any level of acidity may be responsible for mucosal damage seen with the complication of intracranial pathology known as Cushing's ulcer.

Gastric secretory response to head injury.

The problem of stress was studied clinically and in the laboratory. Ten of 19 patients comatose following severe cerebral trauma showed evidence of gastric acid hypersecretion within the first week posttrauma. Three of the ten bled briefly from presumed stress ulcer. Hypersecretion was reduced in three patients after administration of a parasympatholytic drug. Acid hypersecretion occurred both in patients with and without corticosteroid therapy. The Cushing's ulcer appears to differ from other forms of stress in having a higher incidence of associated gastric hyperacidity. Neostigmine bromide, pilocarpine hydrochloride, vitamin A, and phytohemagglutinin failed to stimulate mucus secretion when used topically in gastric pouches. The concept of a topical mucigogue for use in stress patients remains to be established.

The surgical management of acute gastric mucosal bleeding.

Bleeding from superficial gastric erosions was described for the first time in 1898 by Dieulafoy.¹Since then, our understanding of this condition has increased but little. One of the confusing aspects of this condition is that of semantics. This phenomenon has been variously called "acute erosive gastritis," "acute hemorrhagic gastritis," "Curling's ulcer," "Cushing's ulcer," "acute peptic ulcer," and "stress ulcer." Moreover, because there usually is a break in the continuity of the mucosa (erosion, ulceration, ulcer), often it is labeled "gastric ulcer, bleeding." Also, physicians tend to attribute radiologically negative gastrointestinal (GI) bleeding to "peptic ulceration." As a result, the incidence of this condition is not well known. For instance, in 1964 Sullivan et al²wrote that hemorrhagic gastritis is "... relatively uncommon as a cause of major gastrointestinal bleeding...." Technical improvements in endoscopy have increased the frequency with which a clinical diagnosis of acute gastric mucosal bleeding can

N-3. A Case of “Cushing Ulcer” followed by the Stereotaxic Hypothalamotomy

N-3. A Case of “Cushing Ulcer” followed by the Stereotaxic Hypothalamotomy