Dead Man Returns: The Lazarus Phenomenon ( A second chance)

First, you receive a phone call from the hospital. The officials reveal to you that your loved one has been pronounced dead. What would your reaction be if 2 hours later, the doctor calls you again to tell you that your loved one back alive? Puzzled? Numb? Going to get a second doctor’s opinion whether your loved one is really alive or dead by checking the name once again? Simply overjoyed? Call the doctor again and ask him to use a different stethoscope? Or maybe, call all your friends and relatives to have a “Welcome back, party?”.....Well, a series of perplexed thoughts are sure to run wild in our thoughts if this happens to our families. Of course, the variations, your heart beat rate and the intensity differs from individuals. 

Imagine the joy, of having to call out your relatives and friends again to notify that your loved dead is back from the dead. As for their reaction, your guess is as good as mine. After all, some would still want to see him/her and pat on the back and may want to say, “Hey, your lifeline has just been renewed and extended for an indefinite period of time, don't screw up your life and health with your second chance.”

...It’s called the Lazarus Phenomenon (sometimes called Lazarus syndrome) , and goes to prove what a fantastic machine the human body really is.

What is Lazarus Phenomenon?

The Lazarus phenomenon is described as delayed “Return Of Spontaneous Circulation” (ROSC) after cessation of cardiopulmonary resuscitation (CPR). This was first reported in the medical literature in 1982, and the term Lazarus phenomenon was first used by Bray in 1993. The term was coined from the story of Lazarus, who was resurrected by Jesus Christ four days after his death.

Even though Lazarus phenomenon is rare, it is probably under reported. There is no doubt that Lazarus phenomenon is a reality but so far the scientific explanations have been inadequate. So far the only plausible explanation at least in some cases is auto-positive end-expiratory pressure (PEEP) and impaired venous return. In patients with pulseless electrical activity (PEA) or asystole, dynamic hyperinflation should be considered as a cause and a short period of apnoea (30-60 seconds) should be tried before stopping resuscitation. Since ROSC occurred within 10 minutes in most cases, patients should be passively monitored for at least 10 minutes after the cessation of CPR before confirming death.

Case Report

A 66-yr-old man, weighing 80 kg, was emergently brought to the operating room (OR) with a suspected leaking abdominal aortic aneurysm. His past history included hypertension and a transient ischemic attack 4 yr earlier. He also had a 50-pack/yr smoking history and chronic renal insufficiency (creatinine 2.3 mg/dL). He had no history of metabolic disorder. He had received 2600 mL of lactated Ringer’s solution before arrival in the OR. Vital signs on arrival included a heart rate of 120 bpm and a systolic blood pressure of 60 mm Hg. The patient was pale, mottled, diaphoretic, and tachypneic. Rapid administration of warmed IV fluids via two rapid infusion systems increased his systolic blood pressure to 120 mm Hg.

Induction of anaesthesia proceeded uneventfully with d-tubocurarine 3 mg, fentanyl 250 μg, etomidate 20 mg, and succinylcholine 160 mg IV before rapid sequence endotracheal intubation. Maintenance of anesthesia included inhalation of isoflurane (as tolerated by blood pressure) in 100% oxygen. Pancuronium 6 mg was given for continued neuromuscular blockade. With induction of anesthesia, the vital signs remained stable (systolic blood pressure 110–120 mm Hg by automated cuff pressure) and surgical incision promptly followed at 5.30 p.m. An arterial blood gas drawn at this time revealed hemoglobin 8.1 g/dL, K⁺ 3.8 mEq/L, glucose 185 mg/dL, pHa 7.24, PaCO₂ 41 mm Hg, PaO₂ 479 mm Hg, HCO₃16 mEq/L, and base excess −10.6 mEq/L. At this time, the end-tidal CO₂ was 29 mm Hg. Electrocardiogram (ECG) showed a cardiac rhythm of sinus tachycardia.

At 5.48 p.m. the surgeon placed a cross-clamp across the suprarenal aorta. This led to an increase in systolic pressure to 160 mm Hg, but no apparent changes on the ECG. At 5.53 p.m. the clamp was shifted to an infrarenal position. At 5.59 p.m., the cardiac rhythm suddenly deteriorated into ventricular tachycardia, which rapidly progressed to ventricular fibrillation. Chest compressions were initiated, and the patient was ventilated with 100% oxygen. This resuscitation continued for the next 17 min during which time the patient received a total of nine countershocks of 360 J each. Additionally, a total of 5 mg of epinephrine, 4 mg of atropine, 2 g of CaCl₂, 400 mg of lidocaine, 150 mEq of NaHCO₃ and 2 g of MgSO4 were given IV. Chest compressions were initially thought to be effective as the end-tidal CO₂was maintained at 25–32 mm Hg. No arterial line was yet available to observe a waveform or to draw blood gases, and no single-stick arterial blood gas was drawn during the resuscitation. Despite the resuscitation efforts, the underlying rhythm continued to be asystole. This was confirmed by the palpation of a flaccid and pulseless (in the absence of chest compressions) proximal aorta. End-tidal CO₂ had diminished to 8–10 mm Hg, and the pupils were widely dilated. Because of the patient’s complete lack of response and the apparent deterioration by end-tidal CO₂, the attending surgeon and anesthesiologist mutually agreed to discontinue the resuscitation. The patient was pronounced dead at 6.17p.m.

With cessation of the resuscitation, the IV medications and infusions were discontinued. The monitors were turned off, and the ventilator was disconnected although the endotracheal tube was left in situ. The surgeon stayed at the operating table, using the opportunity to teach residents and students. At 6.27p.m., 10 min after the pronounced death of the patient, the surgeon announced that he had begun to feel a pulse in the proximal aorta above the level of the aortic cross-clamp. Ventilation with 100% oxygen was recommenced and revealed an end-tidal CO₂ of 29 mm Hg. The ECG was reconnected and showed a sinus rhythm of 90 bpm. Systolic blood pressure was 90 mm Hg by automated cuff. A radial arterial line was now inserted successfully, and at 0630, arterial blood gases were: hemoglobin 9.5 mg/dL, K⁺ 3.5 mEq/L, glucose 323 mg/dL, pHa 7.17, PaCO₂ 54.4 mm Hg, PaO₂ 438 mm Hg, and base excess −8.0 mEq/L. An esophageal temperature probe was inserted and measured 33.4°C. It was decided to proceed with the operation although neurologic prognosis was anticipated to be bleak. The patient was hemodynamically stable throughout the remainder of the procedure, requiring no inotropic support. Total fluid administration for the operation was 16 U of packed red blood cells, 8 U of fresh frozen plasma, 20 U of platelets, and 12 L of crystalloid solutions. Despite warming of all IV fluids and blood products and the use of a forced air warming blanket, the patient’s temperature ranged between 33° and 34°C for the remainder of the operation. The leaking aneurysm was resected uneventfully and the patient was transported to the intensive care unit.

Postoperatively, the patient was maintained on mechanical ventilation for several days in the intensive care unit. The postoperative course was complicated by mild renal insufficiency and two bouts of atrial arrhythmias (both of which were self-limiting). Remarkably, the patient improved dramatically and, after tracheal extubation, was found to be completely neurologically intact. He appeared to have no short- or long-term memory deficits. He also had no recall of any events of the day of operation except for being initially brought into the OR.

He was discharged home on postoperative Day 13 in excellent condition with no apparent neurologic deficit. Follow-up at 5 wk revealed that the patient had fully recovered, and had resumed full physical activities and his lifestyle of prior to the surgery.

PROPOSED MECHANISMS

The exact mechanism of delayed ROSC is unclear and it is possible that more than one mechanism is involved. Dynamic hyperinflation of the lung causing increased positive end expiratory pressure (PPEP) is one of the proposed mechanisms, which has some supporting evidence in patients with obstructive airways disease.

Positive end expiratory pressure

Rapid manual ventilation without adequate time for exhalation during CPR can lead to dynamic hyperinflation of lungs. Dynamic hyperinflation may lead to gas trapping and an increase in the end-expiratory pressure (called auto-PEEP) leading to delayed venous return, low cardiac output and even cardiac arrest in patients with obstructive airways disease.

The link between mechanical ventilation of patients with obstructive ventilatory defects and circulatory failure was first demonstrated in 1982. One report describes a patient with respiratory failure due to asthma whose blood pressure was undetectable five minutes after initiating artificial ventilation with a tidal volume of 700 mL and respiratory rate of 25 breaths per minute. Even after inotropes the systolic blood pressure did not exceed 70 mm Hg. The ventilator was adjusted to a respiratory rate of six breaths per minute and a tidal volume of 400 mL and the blood pressure gradually rose to 126/84 mm Hg.

The physiology of severe auto-PEEP is similar to pericardial tamponade, where circulation can only be restored after removing the obstacle to cardiac filling. Auto-PEEP is a possible cause of pulseless electrical activity (PEA), and rapid ventilation during CPR should be avoided. Hypovolaemia and decreased myocardial contractility could exaggerate its effect on venous return and cardiac output. Some authors recommend discontinuing the ventilation transiently for 10 to 30 seconds in PEA to allow venous return.

It is tempting to apply this theory even to patients without obstructive airways disease. Dynamic hyperinflation can theoretically happen in any situation where rapid manual ventilation is carried out. One could argue that in the presence of decreased cardiac output—as in myocardial infarction and hypovolaemia—dynamic hyperinflation could compromise the cardiac output even more, leading to cardiac arrest.

Even though auto-PEEP due to dynamic hyperinflation seems most plausible and has some evidence in patients with obstructive airways disease, this alone would not explain all cases of delayed ROSC. In one report, CPR was terminated after 30 minutes and the patient was in asystole. Because the patient had MRSA and CPR was performed without proper infection control measures, the physician involved in the CPR went to shower and change clothes, leaving the patient still being ventilated in the intensive care unit. Returning five minutes later, he found the patient with a perfusable rhythm. The patient died two days later.

Delayed action of drugs          

Some authors suggest delayed action of drugs administered during CPR as a mechanism for delayed ROSC. It is possible that drugs injected through a peripheral vein are inadequately delivered centrally due to impaired venous return, and when venous return improves after stopping the dynamic hyperinflation, delivery of drugs could contribute to return of circulation. In some cases, however, drugs are actually administered through a central line. Even though this theory is plausible it would be impossible to either prove or disprove.

Hyperkalaemia

There are few reports of delayed ROSC in the presence of hyperkalaemia. It is a well-known fact that intracellular hyperkalaemia could persist longer, rendering the myocardium retractile for long periods of time. There is a report on a 68-year-old lady with cardiac arrest due to hyperkalaemia who did not respond to CPR and conventional treatment up to 100 minutes, but later responded to dialysis and made a complete recovery. So even though prolonged cardiac arrest refractory to conventional treatment could respond to dialysis, it is unlikely that hyperkalaemia on its own could explain delayed ROSC after cessation of CPR.

Myocardial stunning

Prolonged myocardial dysfunction can occur following myocardial ischaemia, taking up to several hours before normal function returns. Of the 38 cases, 13 had myocardial infarction, and at least seven had hypovolaemia which could have contributed to transient myocardial ischaemia and stunning.

Transient asystole

Asystole or PEA following countershock of prolonged VF is common and occurs in around 60% of patients. Even though restoration of circulation occurs in 16% of patients, the prognosis is poor: only 0-3% are discharged alive. It is possible that asystole or PEA after countershock could be transient before a perfusable rhythm restores circulation. Transient asystole following defibrillation would explain at least one case, where CPR was interrupted after a last cardioversion attempt resulting in asystole, and ROSC occurred soon after. However, transient asystole would not explain delayed ROSC in majority of patients in whom the duration of asystole was much longer. In another case, CPR was stopped while the patient was still in ventricular fibrillation and haemodynamic activity returned few moments later. The authors of the case rightly point out that CPR should not be halted in a patient with ventricular fibrillation.

CONSEQUENCES OF DELAYED RETURN OF SPONTANEOUS CIRCULATION

Delayed ROSC can lead to serious professional and legal consequences. Questions will be asked about whether CPR has been conducted properly and whether it was stopped too soon. The medical team might be accused of negligence and incompetence and even be sued for damages if a patient survives with severe disability. A doctor involved in resuscitation and certification of death followed by delayed ROSC has recently been accused of culpable homicide.

The conduct of ALS can only be assessed from the case record, so it is vital to record the events during cardiac arrest as accurately as possible. When to discontinue CPR is still a medical decision and so it is absolutely essential to get a consensus from the arrest team and to document the reason for termination of CPR. Some authors recommend measurement of end-tidal carbon dioxide during CPR. Values above 10-15 mmHg indicate a favourable prognosis and should preclude termination of CPR. This technology is not widely available outside the intensive care setting, but should be considered in difficult clinical situations. Whether this would identify patients in whom delayed ROSC might occur is nevertheless questionable.

HOW WOULD ONE RECOGNIZE DEATH?

It is important to realize that death is not an event, but a process. The conference of Medical Royal Colleges in the UK advocated that death is a process during which various organs supporting the continuation of life fail. Cessation of circulation and respiration is such an example. The physical findings to support this—absence of heartbeat and respiration—are the traditional and the most widely used criteria to certify death. Since these findings alone are not a sign of definitive death, it is quite possible to declare death in the interval between cessation of CPR and delayed ROSC.

Because delayed ROSC occurred within 10 minutes in most cases, many authors recommend that patients should be passively monitored for at least 10 minutes following unsuccessful CPR. During that period the family should be informed that CPR had been stopped because of poor response and further efforts are not in the best interests of the patient. It should also be mentioned that the patient is being closely monitored to establish death beyond any doubt. Death should not be certified in any patient immediately after stopping CPR, and one should wait at least 10 minutes, if not longer, to verify and confirm death beyond doubt. This is in line with what was said by W H Sweet in 1978:‘ the time honoured criteria of the stoppage of the heart beat and circulation are indicative of death only when they persist long enough for the brain to die.

NON-MEDICAL LITERATURE

Newspapers

In addition to medical literature, there are many newspaper articles, websites and a few anecdotes in medical journals describing patients who were certified dead, but later found to be alive. Many of these articles refer to these incidents as ‘Lazarus phenomenon’. There is even a movie called Lazarus phenomenon describing two cases of resurrection after death. However, the authenticity of one of these cases has been questioned.

Websites

A website (www.snopes.com/horrors/gruesome/buried.asp) describing people who have been buried alive by mistake in the last few centuries provides entertaining reading. In olden days a number of illnesses could cause coma and there was a danger of hasty disposal of the body especially in those with infectious diseases.

Literature

Edgar Allan Poe's most hair-raising tale is The Premature Burial, in which a young wife was incorrectly pronounced dead and kept in a coffin in the family vault. When the vault was opened a few years later to receive another coffin, a shrouded skeleton was found in the doorway suggested that the lady had survived and eventually died unable to open the vault door. It is believed that he based his story on a widely reported incident that took place around that time.

It seems that the chances of being buried alive were not so remote in 1800s. The fear of being buried alive was so prevalent that many people specified in their wills that tests must be carried out to confirm their death, such as pouring hot liquids on the skin, touching the skin with red-hot irons, or making surgical incisions prior to the burial. A coffin was invented and patented in 1897 to allow a person accidentally buried alive to summon help through a system of flags and bells. The fear of being buried alive is called ‘taphophobia’ in the medical literature. There was even a Society for the Prevention of Burial Before Death, which recognized the difficulties in diagnosing death and issued educational leaflets to assist members of the society.

LAZARUS IN OTHER CONTEXTS

The term Lazarus has also been used to describe many other unexpected and scientifically unexplainable phenomena. Lazarus complex describes the psychological sequence in the survivors of cardiac arrest, near-death experiences and unexpected remission in AIDS. Lazarus syndrome is described in paediatric palliative care, when a child is expected to die but unexpectedly goes into remission. Spontaneous movement in brain dead and spinal cord injury patients has been described as Lazarus sign. Survival of species after mass extinction has been called Lazarus effect. The term Lazarus phenomenon was also used for unexpected survival of renal graft patients.

Lazarus premonition describes an unexpected state of brief resurrection in terminally ill patients, when they experience an increase in vitality, appetite and general improvement. This was recognized at least a thousand years ago in the medieval Chinese literature and was described as hui guang fan zhao, meaning reflected rays of setting sun. Recently a ‘Lazarus Pill’ (Zolpidem, a non-benzodiazepine sedative) has aroused medical interest in patients with persistent vegetative state. This was following a report where a patient with persistent vegetative state showed a brief remarkable neurological response to zolpidem.

RESURRECTION

There are many other resurrections in addition to that of Lazarus. Three resurrections are recorded in the Old Testament, one each by Elijah, Elisha and Elisha's bones. There are many resurrections in the New Testament, four by Jesus (including Lazarus) and one each by Paul and Peter. In Hindu mythology Sathyavan's wife Savithri convinces the Lord of death (Yamaraj) to resurrect Sathyavan following his death after being caught under a falling tree. These stories illustrate that humanity's preoccupation with death and resurrection is universal. The greatest example of Lazarus phenomenon is probably the death and resurrection of Jesus Christ himself.

KEY POINTS

·        Lazarus phenomenon is described as delayed ROSC after cessation of CPR;

·        Dynamic hyperinflation should be considered as a reversible of cause of PEA;

·        Patients should be observed for at least 10 minutes using blood pressure and ECG monitoring after the cessation of CPR before confirming death.

Orofacial manifestations of hematological disorders: Anemia and hemostatic disorders

Abstract

The aim of this paper is to review the literature and identify orofacial manifestations of hematological diseases, with particular reference to anemias and disorders of hemostasis. A computerized literature search using MEDLINE was conducted for published articles on orofacial manifestations of hematological diseases, with emphasis on anemia. Mesh phrases used in the search were: oral diseases AND anaemia; orofacial diseases AND anaemia; orofacial lesions AND anaemia; orofacial manifestations AND disorders of haemostasis. The Boolean operator "AND" was used to combine and narrow the searches. Anemic disorders associated with orofacial signs and symptoms include iron deficiency anemia, Plummer-Vinson syndrome, megaloblastic anemia, sickle cell anemia, thalassaemia and aplastic anemia. The manifestations include conjunctiva and facial pallor, atrophic glossitis, angular stomatitis, dysphagia, magenta tongue, midfacial overgrowth, osteoclerosis, osteomyelitis and paraesthesia/anesthesia of the mental nerve. Orofacial petechiae, conjunctivae hemorrhage, nose-bleeding, spontaneous and post-traumatic gingival hemorrhage and prolonged post-extraction bleeding are common orofacial manifestations of inherited hemostatic disorders such as von Willebrand's disease and hemophilia. A wide array of anemic and hemostatic disorders encountered in internal medicine has manifestations in the oral cavity and the facial region. Most of these manifestations are non-specific, but should alert the hematologist and the dental surgeon to the possibilities of a concurrent disease of hemopoiesis or hemostasis or a latent one that may subsequently manifest itself.

Orofacial Manifestations of Anemia

Iron deficiency anemia

Iron deficiency anemia is the most common hematological disorder. It may manifest in the orofacial region as atrophic glossitis, mucosal pallor and angular cheilitis. Atrophic glossitis "flattening of the tongue papillae" resulting in a smooth and erythematous tongue may mimic migratory glossitis (Table 1). Migratory glossitis, also known as geographic tongue, is a condition of unknown etiology that affects 12% of the population. It results in lesions on the tongue that are erythematous, non-indurate, atrophic and bordered by a slightly elevated, distinct rim that varies in color from gray to white. In atrophic glossitis, these areas do not have a white keratotic border and they increase in size rather than changing in position. In more severe cases, the tongue may be tender. Angular stomatitis (painful fissures at the corners of the mouth) and cheilosis (dry scaling of the lips and corners of the mouth) are also common findings associated with iron deficiency anemia. Angular cheilitis, however, is often associated with fungal infections (Candida albicans), lip-sucking and dehydration. Treatment must focus on correcting the deficiency state and providing adequate energy, protein, fluids and nutrients to promote healing. When angular cheilitis is due to opportunistic infections brought on by decreased resistance secondary to nutrient deficiencies, treatment should focus on antifungal therapy, correction of the nutrient deficiency and diet modification to make eating a more comfortable experience.

Table 1: Orofacial manifestations of anemias

The  Plummer-Vinson syndrome

This is otherwise called the Patterson-Brown-Kelly syndrome or sideropenic dysphagia. It is a symptom complex caused by iron deficiency. This syndrome manifests as atrophic glossitis, or angular cheilitis, and, occasionally, hyperkeratotic lesions are seen in the oral mucosa. It is also associated with koilonychias (or spoon nails), pagophagia and dysphagia due to pharyngoesophageal ulcerations and esophageal webs.

Megaloblastic anemia

This may be caused by a vitamin B12 deficiency (commonly from pernicious anemia, surgical resection of the ileum or small intestinal diverticula) or by a folic acid deficiency (most commonly from malnutrition). Vitamin B12 deficiency manifests in the oral cavity as part of megaloblastic changes in the entire gastrointestinal tract, which are so well demonstrated morphologically in the bone marrow. The oral manifestations of painful atrophy of the entire oral mucous membranes and tongue (glossitis), stomatitis as well as mucosal ulceration (recurrent aphthous ulcers) in vitamin B12 and folate deficiency have long been recognized (Table 1). These oral changes may occur in the absence of symptomatic anemia or of macrocytosis. "Magenta tongue," which is said to be rather characteristic, may herald a B12 deficiency. 

Sickle cell anemia

Sickle cell disease is generically used to describe a group of disorders characterized by the production of abnormal hemoglobin S (HBS). The entities include sickle cell anemia (HbSS), sickle cell Hb C disease (HbSC) and sickle cell-β thalassaemia.

Sickle cell anemia (HbSS) is the most common type and represents the homozygous form where the individuals inherit a double dose of the abnormal gene that codes for hemoglobin S. The sickle hemoglobin abnormality is caused by substitution of valine for glutamic acid in the sixth position from the NH ₂ terminal end of the β-globin chain. With decreased oxygen tension, the abnormal hemoglobin polymerizes, forming fluid polymers (tactoids) that cause the red cells to deform into a characteristic sickle shape that may plug different areas of the microcirculation or large vessels.

The hallmark features of sickle cell disease are chronic hemolytic anemia and vaso-occlusion resulting in ischemic tissue injury. While a wide spectrum of complications result from these, the major manifestation of concern is "sickle crisis" of aplastic, hemolytic or painful (vaso-occlusive) types leading to devastating multisystem complications, including stroke, pulmonary disease, delayed growth, osteomyelitis, organ damage and psychosocial dysfunction. All tissues and organs within the body are at risk of damage due to sickling.

Although relatively uncommon, a number of orofacial changes have also been observed in sickle cell disease. When it occurs, the basic pathogenicity is similar to that in other organs. These orofacial changes in HbSS as reported in the literature include midfacial overgrowth attributable to marrow hyperplasia, other skull and jaw changes such as increased thickening of the skull and osteoporotic changes, mandibular infarction that may be followed by osteosclerosis,  osteomyelitis of the mandible, anesthesia or paraesthesia of the mental nerve, asymptomatic pulpal necrosis, orofacial pain, enamel hypomineralization and diastema (Table 1). These dentofacial deformities are radiographically characterized by a step-ladder appearance of the alveolar bone and areas of decreased densities and coarse trabecular pattern most easily seen between the root apices of the teeth and the inferior border of the mandible.

Mandibular osteomyelitis is an oral complication commonly observed in patients with sickle cell anemia, which is rarely manifested with other complications, making both its diagnosis and treatment easy. The mandible is the most affected part of the face because the blood supply is relatively insufficient when compared with the maxilla. Intravascular impairment can result in both ischemic infarct and osteonecrosis thus allowing bacterial proliferation by Streptococcus or  Salmonella  Aches in the mandible can be preceded by widespread painful crises and be accompanied by neuropathy involving the inferior alveolar nerve and paraesthesia of the lower lip.

The possibility of blood extravasations and hematoma secondary to sickle cell anemia-induced hemorrhage should be considered as a working diagnosis of a facial swelling in sickle cell disease. Scipio et al. reported a case of a 14-year-old boy with sickle cell-related hemorrhage who developed an acute facial swelling, mimicking facial cellulitis of dental origin. Surgical exploration, however, revealed a large hematoma between the periosteum and the lateral aspect of the ramus of the mandible. Pools of blood were also found within the buccinators muscle. The boy also exhibited gingival enlargement, which was considered to be an outcome of repeated hemorrhagic episodes and fibrous repair. Gingival biopsies reported the presence of erythrocyte-filled intraepithelial blood vessels in the gingival epithelium.

Saint Clair de Velasquez and Rivera reported, in a study, that the most common soft tissue oral manifestation of sickle cell anemia in a Venezuelan population was buccal mucosa pallor, while the most common hard tissue finding was enlarged medullary spaces.

The increased number of malocclusions in patients with sickle cell disease can be related to muscular imbalance, absence of labial sealing or changes in the osseous base thus leading to increased orthodontic intervention.

Thalassaemia

These are a group of inherited hemolytic anemia involving defects in the synthesis of either the αor the β polypeptide chains of hemoglobin (α-thalassaemia, β-thalassaemia). Based on genetic and clinical entities, thalassaemia are classified as homozygous, heterozygous or compound heterozygous. The heterozygous form of the disease (thalassaemia minor) is mild and usually asymptomatic, the only manifestation being hypochromic microcytic anemia.

Homozygous β-thalassaemia, also known as Cooley's anemia or Mediterranean anemia, is chiefly seen in Mediterranean populations with prevalence as high as 15-20% in Greece, Turkey, Cyprus and southern Italy.

The homozygous form of β-thalassaemia (thalassaemia major) exhibits the most severe clinical symptoms with marked orofacial deformities. The onset of symptoms occurs early in infancy and the patients are severely anemic and have a short life expectancy. Patients with the most severe form of the disease rarely survive into adulthood because of cardiac failure, chronic anemia and hypoxia. However, with modern management, the prognosis has greatly improved.

The most common orofacial manifestations are due to intense compensatory hyperplasia of the marrow and expansion of the marrow cavity (Table 1) and a facial appearance known as "chipmunk" face: enlargement of the maxilla, bossing of the skull and prominent molar eminences. Overdevelopment of the maxilla frequently results in an increased over jet and spacing of maxillary teeth and other degrees of malocclusion.

Aplastic anemia

Aplastic anemia commonly presents with oral manifestation and can be the first clinical manifestation of the disease (Table 1). The most common orofacial manifestation of the disease is multiple hemorrhages, which most often develop in patients with platelet counts <25 × 10 ⁹ /liter. (Figure 1) a and b shows multiple orofacial hemorrhages in a 12-year-old patient with aplastic anemia. The other common manifestations are oral ulceration, candidiasis and viral infection. 

Figure 1: (a) A 12-year-old boy with aplastic anemia. Note the subconjunctival ecchymosis. (b) The same patient as in Figure 1a. Note ecchymosis of the lower lip and cheek as well as sublingual hematoma

Orofacial manifestations of disorders of hemostasis

Interaction of several basic mechanisms produces normal hemostasis, which can be divided into four general phases: the vascular phase; the platelet phase; the coagulation cascade phase, consisting of intrinsic, extrinsic and common pathways; and the fibrinolytic phase. 

An abnormal tendency to hemorrhage or thromboembolism occurs in the mixed group of disorders known as hemostatic disorders. All hemorrhagic hemostatic disorders, both inherited and acquired, may produce a variety of orofacial manifestations, including petechiae, nose bleeding, spontaneous and post-traumatic gingival hemorrhages and prolonged post-extraction bleeding (Table 2). Minimal trauma, such as occurs in eating or in tooth brushing, may be sufficient to provoke gingival hemorrhage, which, when it does, is characterized by its persistence rather than its profusion, and the total volume of blood loss may be important. 

Table 2: Orofacial manifestation of some disorders of hemostasis

Vascular disorders of hemostasis

The vascular disorders are a heterogenous group of conditions characterized by easy bruising and spontaneous bleeding from the small vessels. Frequently, the bleeding is mainly in the skin, causing petechiae, ecchymoses or both and in some cases there is bleeding also from the mucous membrane. Vascular defect of hemostasis may be acquired or inherited. Most cases of bleeding from the vascular defect alone are not severe or life threatening. Hereditary hemorrhagic telangiectasia  and  Ehlers-Danlos syndrome in which some patients express the characteristic facial appearance of large eyes, small chin, thin nose and lips, lobeless ears are examples of hereditary vascular disorders that may present with petechiae or ecchymotic lesions on the lips, tongue and oral mucosa and epistaxis.

Platelet disorders in hemostasis

Abnormal bleeding associated with thrombocytopenia (low platelet count) or abnormal platelet function is characterized by spontaneous skin purpura, mucosal hemorrhages and prolonged bleeding after trauma.

Facial petechiae, conjunctivae hemorrhage and hemorrhagic bullae in the oral mucous membrane occur in primary deficiency of platelets. These features are also seen in secondary thrombocytopenia due to the myelophthisic syndrome, autoimmune disorder, aplastic anemia (Figure 1) a and b, infections, collagen vascular disease, disseminated intravascular coagulopathy and drugs. These features may be seen in von Willebrand's disease (VWD) and have also been observed in severe hemophilia.

Thrombocytopenia secondary to an autoimmunologic disorder is called idiopathic thrombocytopenic purpura (ITP). It is an autoimmune disease characterized by the production of antibodies against ones own platelets. These antibodies adhere to the platelets and are recognized and destroyed by the reticuloendothelial system. Consequently, the platelet count gradually diminishes and is insufficient for the maintenance of primary hemostasis. Several reports have documented cases of ITP presenting as post-extraction hemorrhage.

Disorders of platelet function are suspected in patients who show skin and mucosal hemorrhages and in whom the bleeding time is prolonged despite a normal platelet count. Glanzmann thrombasthenia (GT) is an exceedingly rare but well-defined inherited disorder of platelet function caused by a defect in the glycoprotein IIb/IIIa complex. The association of GT with consanguinity has been noted, especially in geographic regions in which such intermarriage is common. In most patients, GT is diagnosed during early infancy or before the age of 5 years. Common manifestations of this hemorrhagic disorder are gingival hemorrhage, purpura, epistaxis, petechiae and menorrhagia. Bernard-Soulier syndrome and grey platelet syndrome are the other well-defined, inherited disorders of platelet function while the use of antiplatelet drugs like aspirin and clopidogrel, uremia and hyperglobulinemia are some acquired disorders of platelet function with similar orofacial manifestations.

Coagulation disorders of hemostasis

In the 2007 World federation of hemophilia global survey where 89% of the world population was covered, 52,545 persons were identified with VWD, 105,018 with hemophilia A, 21,384 with hemophilia B, while 18,762 persons were identified with other bleeding disorders. In this survey, the total number of people identified with bleeding disorders was 213,904.

von Willebrand's disease

VWD is one of the most common hereditary coagulation abnormalities in humans and shows a worldwide distribution.  It is classified into type 1, type 2A, 2B, 2M, 2N disease. Type 1 disease is the most common form of VWD, accounting for approximately 80% of all cases. It is transmitted as an autosomal-dominant trait and thus there may be evidence of a family history of excessive bleeding. Most forms of the disease show incomplete penetrance of the phenotype and variable expressivity of bleeding symptoms within families. In contrast, the severe type 3 form of the disease shows a recessive pattern of inheritance with parents that do not usually manifest clinical symptoms. Type 2N VWD, in which isolated low FVIII levels occur, also shows a recessive pattern of inheritance and, thus, here again, a family history may be absent.

The diagnosis of VWD is established by finding a prolonged bleeding time, a low level of factor VIII procoagulant activity and abnormally low levels of factor VIII - von Willebrand protein by immunologic assay and diminished platelet aggregation in response to ristocetin. The clinical bleeding symptoms of this disorder are notoriously heterogeneous and may range from virtually no symptom to mild symptoms to a disease resembling factor VIII deficiency and include oral mucosal bleeding, soft tissue hemorrhage, menorrhagia in women and rare hemarthrosis. Continuous oral bleeding over long periods of time fosters deposits of hemosiderin and other blood degradation products on the tooth surfaces, turning them brown. If the history suggests VWD and oral surgery is contemplated in these patients, hematology consultation should be obtained and the patient's blood should be typed.

Hemophilia

Hemophilia is an X-linked hereditary disorder. Hemophilia A is a deficiency of factor VIII while hemophilia B (Christmas disease) is a deficiency of factor IX. Factors VIII and IX are important in the intrinsic phase of blood coagulation and their deficiency is considered severe when plasma activity of the deficient factor is <1 IU/dl (normal range, 50-100), moderate if it ranges between 2 and 5 IU/dl and mild if it is between 6 and 40 IU/dl.

The deficiency of factors VIII and XI is characterized by bleeding from multiple sites, frequently manifested in the mouth as gingival and post-extraction hemorrhages. Hemophiliacs may experience many episodes of oral bleeding over their lifetime. Sonis and Musselman reported an average 29.1 bleeding events per year, serious enough to require factor replacement in F VIII-deficient patients, of which 9% involved oral structures. Location of oral bleeding according to Sonis and Musselman are labial frenum, 60%; tongue, 23%; buccal mucosa, 17%; gingiva and palate, 0.5%. Bleeding occurrences were most frequent in patients with severe hemophilia, followed by moderate and then mild hemophilia, and most often resulted from traumatic injury. Bleeding events may also be induced by poor oral hygiene practices and iatrogenic factors. Kaneda and colleagues  reported frequency of oral hemorrhage by location in individuals' deficient of F VIII and F IX as follows: gingiva, 64%; dental pulp, 13%; tongue, 7.5%; lip, 7%; palate, 2%; buccal mucosa, 1%. Many minor oral bleeds, such as those from the gingiva or dental pulp, can be controlled by local measures while more major forms will require factor replacement.

Hemarthrosis is a common complication in a hemophiliacs' weight-bearing joints, yet it rarely occurs in the temporomandibular joint (TMJ). There are very few reported case of TMJ hemarthrosis. Chronic hemophilic TMJ arthropathy may also occur, which requires arthrotomy, arthroscopic adhesion lysis, factor replacement, splint therapy and physical therapy. The treatment of patients with either hemophilia A or hemophilia B involves the replacement of the deficient clotting factors by intravenous infusion to either control or prevent bleeding. Patients with mild factor VIII deficiency may be treated with DDAVP to raise the factor VIII level.

There is a group of rare inherited coagulation disorders that may present significant difficulties in diagnosis and management,  and with similar orofacial manifestations of hemophilia and VWD. These rare disorders include defects of fibrinogen, prothrombin, factor V, combined deficiency of factors V and VIII, factor VII, factor X, deficiency of vitamin K-dependent factors (II, VII, IX, X), factor XI, factor XII and factor XIII deficiency. The overall frequency of these disorders in the general population is low (with the exception of factor XI deficiency). Homozygous deficiency varies from 1 in 500,000 for factor VII deficiency to 1 in 2 million for prothrombin. All the disorders are autosomally inherited and, with the exception of factor XI deficiency, generally have no significant clinical manifestations in heterozygotes. Severe deficiencies are more likely to be found in populations where marriage between blood relatives is common and, in rare cases, individuals may inherit more than one disorder.

Factor XI deficiency, also known as hemophilia C, is the most common of the rare disorders and has a more variable bleeding tendency than hemophilia A or B. The deficiency is particularly common in Ashkenazi Jews, where the carrier rate is 8-9%. Severely deficient individuals (FXI<10 IU/dl) have a mild bleeding tendency after surgery, especially in areas with high fibrinolytic potential such as the mouth, the nose and the genitourinary tract. Spontaneous bleeding is rare, and hemarthroses are not a feature.

Preventive and restorative dental care, particularly for the patient with hereditary hemostatic disorder, is of paramount importance for the fact that advanced dental conditions and subsequent treatments have proven to be more complicated and risky. Quite often, dental health is neglected by hemophiliacs for fear of bleeding during procedures. Surprisingly, even dental specialists avoid these candidates and contribute to the conversion of a simple dental patient to an oral surgical patient.  The complexities involved in diagnosing a bleeding disorder and the rarity of a standardized protocol to handle such patients contribute to this problem.

Conclusion

A wide array of disorders of red cells and hemostasis encountered in internal medicine has manifestations in the oral cavity and the facial region. Most of these manifestations are non-specific, but should alert the hematologist and the dental surgeon to the possibilities of a concurrent disease of hemopoiesis or hemostasis or a latent one that may subsequently manifest itself. These manifestations must be properly recognized if the patient must receive appropriate diagnosis and referral for treatment. Proper diagnosis is essential to initiate the correct treatment.

Gorlin-Goltz syndrome

Abstract

Gorlin-Goltz syndrome is an inherited autosomal dominant disorder with complete penetrance and extreme variable expressivity. The authors present a case of an 11-year-old girl with typical features of Gorlin-Goltz syndrome with special respect to medical and dental problems which include multiple bony cage deformities like spina bifida with scoliosis having convexity to the left side, presence of an infantile uterus and multiple odonogenic keratocysts in the maxillofacial region.

Introduction

The Gorlin-Goltz syndrome or nevoid basal cell carcinoma (BCC) syndrome or nevus epitheliomatodes multiplex, or nevoid basal-cell epithelioma-jaw cyst-bifid rib syndrome is an uncommon, autosomal dominant disorder affecting multiple organ systems which include skeletal, eye, skin, reproductive, and neural system, although all the features are rarely observed in a single patient. It is principally characterized by cutaneous BCCs (seen in 50-97% of people with the syndrome), multiple keratocysts (present in 75% of people), and skeletal anomalies. The incidence of this disorder is estimated to be 1 in 50,000 to 150,000 in the general population, varying from region to region. Many of the symptoms were first described by Jarish and White in 1894, while in 1960 Robert J Gorlin and Robert W. Goltz defined the condition as a syndrome comprising the principal triad of multiple basal cell nevi, jaw keratocyst, and skeletal anomalies. It appears in all ethnic groups, but most often in Whites; males and females are equally affected.

Case Report

An 11-year-old female patient attended the Department of Oral and Maxillofacial surgery, Dr. R. Ahmed Dental College and Hospital, with a chief complaint of delay in the eruption of permanent teeth. A brief medical history revealed that during late infancy (11 months) she was diagnosed to have rickets and treated for the same. Apart from this, her past history was uneventful. Her psychomotor development was normal and her school performance was above average.

At the Department the patient was completely examined. On inspection, the patient appeared to have sprengel deformity (Figure 1). AP view of the chest revealed multiple bony cage abnormalities. Significant findings elicited were spina bifida of C5 and C6 vertebrae with scoliosis having convexity to the left side and left and right 4 ^th and 5^th ribs partially fused with narrow intercostal space (Figure 2). Complete blood count was done and appeared to be within normal limits. Panoramic radiograph revealed multiple radiolucent areas in the region suggestive of a cyst (Figure 3). Aspirates of right ramus region of mandible and the biochemical analysis revealed a total protein content of 0.8 g/dl, suggestive of a keratocyst. Enucleation with open dressing (packing the cavity with iodoform gauze) of the right ramus region cyst was done. Enucleation of the left body mandible cyst was done. The cystic lining was sent for histopathologic examination and was confirmed as odontogenic keratocyst.

 Figure 1: Arrow showing sprengel deformity

Figure 2: Arrows showing odontogenic keratocyst

Figure 3: AP chest and neck radiograph showing spina bifida of C5 and C6 vertebrae and partially fused left and right 4th and 5th ribs

The patient was advised to get an ultrasonography of the abdomen which revealed a small nodular structure in uterine fossa giving an impression of an infantile uterus. Left ovary could not be visualized.

The patient was also referred to a tertiary care centre for genetic evaluation where karyotyping from blood was done and no detectable abnormality was elicited.

Based on the clinical, radiographic, and histologic findings, and referring to the diagnostic criteria for nevoid BCC syndrome established by Evans et al, and modified by Kimonos et al. in 1997, the patient was diagnosed as having Gorlin-Goltz syndrome.

Discussion

Gorlin-Goltz syndrome is an autosomal dominant disorder with high penetrance and variable expressivity. It is caused by the mutations in the patched tumor suppressor gene (PTCH), a human homologue of the Drosophila gene mapped to the long arm of chromosome 9q22.3-q31. Gorlin-Goltz syndrome's typical malformative patterns suggest that the main function is to control the growth and development of normal tissues. It is associated with multiple keratocysts in patients in the second decade of their life. In the case presented here, one of the first signs was multiple cystic lesions involving the maxilla and mandible, which have been histopathologically diagnosed as odontogenic keratocysts. The association with odontogenic keratocysts, however, is not clearly understood and appears in more than 90% of the cases. All the other disorders are less frequent. Acral pits that are often overlooked during physical examination have a characteristic dermoscopy with red globules that are mainly distributed in parallel lines inside flesh-colored, irregular-shaped, and slightly depressed lesions. Dermoscopy improves the visualization of these pits.

Despite the name of the syndrome, multiple BCCs occur only in 50% of the cases. They may vary in number from a few to 1000 and range in size from 1 to 30 mm in diameter. BCC most often involves face and non-exposed areas such as the back and chest. Management of superficial BCC without hair follicle involvement can be accomplished by the topical application of 0.1% Retinoin cream, 5% 5-Florouracil cream, 5% Imiquimod cream, cryosurgery, and surgical excision.

The diagnostic criteria for nevoid BCC were established by Evans et al, and modified by Kimonis et al. in 1973. According to them, diagnosis of Gorlin-Goltz syndrome can be established when two major or one major and two minor criteria are present which are described below.

Major criteria

1. More than two BCCs or one BCC under the age of 20 years.
2. Histologically proven odontogenic keratocyst of the jaw.
3. Three or more cutaneous palmar or plantar pits.
4. Bifid, fused or markedly splayed ribs.
5. First degree relative with nevoid basal cell carcinomas.

Minor criteria

This consists of any one of the following features.

1. Proven macrocephaly, after adjustment for height.
2. One of the several orofacial congenital malformations: cleft lip or palate, frontal bossing, 'coarse face', moderate or sever hypertelorism.
3. Other skeletal abnormalities: sprengel deformity, marked pectus deformity, marked syndactyly of the digits.
4. Radiological abnormalities: Bridging of the sella turcica, vertebral anomalies such as hemivertebrae, fusion or elongation of the vertebral bodies, modeling defects of the hands and feet, or flame shaped lucencies of the hands or feet.
5. Ovarian fibroma.
6. Medulloblastoma.

In this article, the authors have presented a case having two major (histologically proven odontogenic keratocyst of the jaw and bifed, fused or markedly splayed ribs) and one minor criteria (sprengel deformity).

Conclusion

Gorlin-Goltz syndrome is an entity that often involves the maxillofacial region. Multiple cyst of jaw may be an indicator of this pathology and may occur as early as 7-8 years of age. It is important to make an early diagnosis and proper management of Gorlin-Goltz syndrome mainly due to its malignant predisposition. The guideline for diagnosis includes a family history, careful oral and skin examination, chest and skull radiographs, panoramic radiographs of the jaws, and pelvic ultrasonography in women. This entity shares its differential diagnosis with cherubism.

Diagnosis and therapy of this syndrome requires a multidisciplinary approach (oral surgeons, dermatologists, surgeons, and neurologists and geneticists). It consists of surgical removal of tumors and adequate treatment of keratocyst. Patients with Gorlin-Goltz syndrome require consistent sun protection. Genetic counseling that considers the genetic risks is advisable for all patients with this syndrome, both familial and sporadic.

References

1.	Manfredi M, Vescovi P, Bonanini M, Porter S. Nevoid basal cell carcinoma syndrome: A review of the literature. Int J Oral Maxillofac Surg 2004;33:117-24.
2.	Ljubenoviζ M, Ljubenoviζ D, Biniζ I, Jovanoviζ D, Stanojeviζ M. Gorlin-Goltz syndrome. Acta Dermatovenerol Alp Panonica Adriat 2007;16:166-9.
3.	Rai S, Gauba K. Jaw cyst-basal cell nevus-bifid rib syndrome: A case report. J Indian Soc Pedod Prev Dent 2007;25:137-9.
4.	Esposito SJ, Kast G, Bradrick JP. Basal cell nevus syndrome: A clinical report. J Prosthet Dent 1995;73:405-10.
5.	Ahmed N, Salman M, Mansoor MA. Gorlin-Goltz syndrome. J Coll Physicians Surg Pak 2007;17:568-9.