Oral vesiculo-bullous lesions By R. HASKELL (London, England) AT one time it was customary to distinguish vesicular (subepithelial) and bullous (intra-epithelial) lesions but now they are often grouped together. These lesions as they affect the mouth may be classified as in Table I. They are characterized by the presence of vesicles or bullae, but in the mouth these break down so rapidly that oral ulceration is the major clinical manifestation. TABLE I. CLASSIFICATION OF VESICULO-BULLOUS DISORDERS
(1) Hereditary Epidermolysis bullosa (2) Viral (a) Primary Herpetic gingivo-stomatitis (b) Zoster " (c) Herpangina (d) Hand-foot and mouth disease (3) Immunological Pemphigus (4) Idiopathic (a) Pemphigoid (b) Erythema multiforme (c) Primary amyloidosis
I shall not discuss epidermolysis bullosa since its main characteristic is extreme rarity, but I would mention that the typical atrophic scars on the knees are the important diagnostic clue. Primary herpetic gingivo-stomatitis is the commonest vesiculo-bullous lesion encountered in the mouth and is surprisingly often overlooked, being misdiagnosed as 'dental abscess', 'teething' or 'Vincents' infection'. It occurs most commonly between the ages of six months and five years and thereafter with diminishing frequency although it is not uncommon in the twenties. The onset is sudden with malaise, fever and extreme soreness in the mouth (in children evidenced by food refusal). Clinical examination reveals the intense oral inflammation which is largely confined to the gingival margin of the attached mucosa. Widespread ulceration of this attached (keratinized) mucosa is also noted although the occasional ulcer may be noted on unattached mucosa, even, exceptionally, spreading on to the facial skin. The ulcers form as a result of breakdown of vesicles and this process is so rapid that at most only one or two intact vesicles may be noted in 101
R. Haskell the mouth. Adjacent ulcers may coalesce to produce large ulcers but typically each ulcer is less than 5 mm. in diameter. Extensive (tender) cervical lymphadenopathy is invariably present. The diagnosis may be confirmed by scraping the base of an intact vesicle and examining the scrapings for typical 'herpetic' nuclear changes in the epithelial cells. Giant 'mulberry' nuclei are seen and occasionally an inclusion (Lipschultz) body. These nuclear changes are found in all herpes virus infections including zoster, but chicken pox, zoster and secondary herpes simplex are readily excluded by the distribution of lesions. The commonest cause of oral ulceration is recurrent oral aphthae. It is not a vesiculo-bullous condition, and these ulcers are almost always on unattached mucosa, in striking contrast to the lesions of herpes. Also, even a severe attack of aphthous ulceration is not attended by fever or systemic upset or cervical lymphadenopathy. If it is not possible to confirm the diagnosis of herpes from oral lesion cytology then retrospective diagnosis can be made from comparing an initial with a convalescent antibody titre. The second lesion due to a herpes virus—zoster—is not uncommon in the distribution of the trigeminal nerve, although of course it preferentially attacks the first division. If the second or third divisions are affected oral lesions appear after the prodomal pain. The lesions are identical to those of primary herpes but are strikingly 'neurological' in distribution and this effects the diagnosis. Other viruses producing oral lesions include the Coxsackie group and there are two distinct clinical pictures. Herpangina is the commonest and may be due to virus subtypes A2, 4, 5, 6, 8, 10 and 22. The symptoms, are of a sore throat, and examination reveals a mass of minute vesicles confined to the soft palate and fauces. These soon break down and ulcerate. The whole episode is past in a week or ten days. The other Coxsackie clinical lesion is Hand, foot and mouth disease which is due to types A16 (or 5 and 9). The oral lesions are so minute as readily to escape detection but the vesicles on the hands and feet are more prominent. For all these viral diseases there is no specific treatment but considerable relief from oral soreness may be obtained by the use of Elixir of tetracycline as a mouth wash four times daily. Tetracycline is specifically contra-indicated in children less than eight years old, and for them erythromycin elixir is a suitable alternative. Pemphigus is the most important of the diseases under consideration because of its potentially lethal nature. It tends to be more frequent in middle-age and in those of Jewish extraction. The disease may present with recurrent oral bullae and the oral lesions may be the only feature for some time before the skin is clinically involved. The oral lesions are usually noted as ulcers but these often have the remains of the roof of the 102
Oral vesiculo-bullous lesions bullae attached at their edges. An important clinical observation is that gentle rubbing causes the lesion to extend, and it is important to ask the patient if the ulcers were preceded by 'blisters'. If pemphigus is considered, the diagnosis must be confirmed as soon as possible. Cells scraped from the base of a bulla or ulcer should be examined for typical acantholytic cells. Biopsy should also be performed and simple light microscopy may be sufficient to establish the diagnosis. Final proof may be obtained by demonstrating that (a) The patient's epithelial cells are coated by immunoglobulin and (b) That his serum contains immunoglobulins that react specifically with the epithelial cells of a normal subject. In both cases the specific auto-antibody is demonstrated by fluorescein-labelled antihuman IgG. Purely oral lesions in pemphigus may be adequately controlled by local steroids but systemic steroids are usually required, and this is the case when generalized disease occurs. Pemphigoid, as might be deduced from its title, may be clinically indistinguishable from pemphigus. The lesions are however subepithelial and tend to 'spread' less. The disease is one of the elderly and is common in females. Lesions tend to be oral and ocular, while they are sparse on the skin. Diagnosis may be effected by biopsy. The specific prickle cell autoantibodies of pemphigus are absent but there may be demonstrable antibody attached to the basement membrane of the epithelium. Treatment is with topical steroids. Erythema multiforme is a rather unusual condition. It is a clinical manifestation which may be produced by allergy to drugs or by infection with Mycoplasma pneumoniae but in most cases the cause cannot be demonstrated. The most severe cases are sometimes unnecessarily distinguished by the eponymous title Stevens-Johnson syndrome. There may be widespread visceral damage since the pathogenesis is in intravascular antigen-antibody reaction. The oral features are of widespread patchy inflammation; at sites of most intense reaction bullous formation occurs, thence ulceration. The lips are invariably involved and become coated by haemorrhagic exudate which is a characteristic feature. The skin is usually affected to a greater extent than oral mucosa. The cause should be established if possible by careful questioning for allergies. If Myco. pneumoniae appears to be the cause as revealed by typical pneumonia then tetracycline is indicated. Otherwise systemic steroids are the mainstay of treatment, with supportive therapy. Finally mention must be made of one of the rarest causes of bullous lesions of the oral mucosa, namely primary amyloidosis. Recurrent small blood-filled bullae occur due to minor trauma and these, although an unusual feature of this condition, are almost pathognomonic. They are useful since biopsy of them will provide diagnostic histopathological material. 103
R. Haskell The causes of oral ulceration are large and varied. The vesiculo-bullous lesions form a subgroup which can usually be distinguished clinically by their named characteristic. Equally each member of the group has distinctive clinical features which I hope this presentation has highlighted. Greenwich District Hospital, Vanbrugh Hill, London, SEio aHE.
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(1) Hereditary Epidermolysis bullosa (2) Viral (a) Primary Herpetic gingivo-stomatitis (b) Zoster " (c) Herpangina (d) Hand-foot and mouth disease (3) Immunological Pemphigus (4) Idiopathic (a) Pemphigoid (b) Erythema multiforme (c) Primary amyloidosis
I shall not discuss epidermolysis bullosa since its main characteristic is extreme rarity, but I would mention that the typical atrophic scars on the knees are the important diagnostic clue. Primary herpetic gingivo-stomatitis is the commonest vesiculo-bullous lesion encountered in the mouth and is surprisingly often overlooked, being misdiagnosed as 'dental abscess', 'teething' or 'Vincents' infection'. It occurs most commonly between the ages of six months and five years and thereafter with diminishing frequency although it is not uncommon in the twenties. The onset is sudden with malaise, fever and extreme soreness in the mouth (in children evidenced by food refusal). Clinical examination reveals the intense oral inflammation which is largely confined to the gingival margin of the attached mucosa. Widespread ulceration of this attached (keratinized) mucosa is also noted although the occasional ulcer may be noted on unattached mucosa, even, exceptionally, spreading on to the facial skin. The ulcers form as a result of breakdown of vesicles and this process is so rapid that at most only one or two intact vesicles may be noted in 101
R. Haskell the mouth. Adjacent ulcers may coalesce to produce large ulcers but typically each ulcer is less than 5 mm. in diameter. Extensive (tender) cervical lymphadenopathy is invariably present. The diagnosis may be confirmed by scraping the base of an intact vesicle and examining the scrapings for typical 'herpetic' nuclear changes in the epithelial cells. Giant 'mulberry' nuclei are seen and occasionally an inclusion (Lipschultz) body. These nuclear changes are found in all herpes virus infections including zoster, but chicken pox, zoster and secondary herpes simplex are readily excluded by the distribution of lesions. The commonest cause of oral ulceration is recurrent oral aphthae. It is not a vesiculo-bullous condition, and these ulcers are almost always on unattached mucosa, in striking contrast to the lesions of herpes. Also, even a severe attack of aphthous ulceration is not attended by fever or systemic upset or cervical lymphadenopathy. If it is not possible to confirm the diagnosis of herpes from oral lesion cytology then retrospective diagnosis can be made from comparing an initial with a convalescent antibody titre. The second lesion due to a herpes virus—zoster—is not uncommon in the distribution of the trigeminal nerve, although of course it preferentially attacks the first division. If the second or third divisions are affected oral lesions appear after the prodomal pain. The lesions are identical to those of primary herpes but are strikingly 'neurological' in distribution and this effects the diagnosis. Other viruses producing oral lesions include the Coxsackie group and there are two distinct clinical pictures. Herpangina is the commonest and may be due to virus subtypes A2, 4, 5, 6, 8, 10 and 22. The symptoms, are of a sore throat, and examination reveals a mass of minute vesicles confined to the soft palate and fauces. These soon break down and ulcerate. The whole episode is past in a week or ten days. The other Coxsackie clinical lesion is Hand, foot and mouth disease which is due to types A16 (or 5 and 9). The oral lesions are so minute as readily to escape detection but the vesicles on the hands and feet are more prominent. For all these viral diseases there is no specific treatment but considerable relief from oral soreness may be obtained by the use of Elixir of tetracycline as a mouth wash four times daily. Tetracycline is specifically contra-indicated in children less than eight years old, and for them erythromycin elixir is a suitable alternative. Pemphigus is the most important of the diseases under consideration because of its potentially lethal nature. It tends to be more frequent in middle-age and in those of Jewish extraction. The disease may present with recurrent oral bullae and the oral lesions may be the only feature for some time before the skin is clinically involved. The oral lesions are usually noted as ulcers but these often have the remains of the roof of the 102
Oral vesiculo-bullous lesions bullae attached at their edges. An important clinical observation is that gentle rubbing causes the lesion to extend, and it is important to ask the patient if the ulcers were preceded by 'blisters'. If pemphigus is considered, the diagnosis must be confirmed as soon as possible. Cells scraped from the base of a bulla or ulcer should be examined for typical acantholytic cells. Biopsy should also be performed and simple light microscopy may be sufficient to establish the diagnosis. Final proof may be obtained by demonstrating that (a) The patient's epithelial cells are coated by immunoglobulin and (b) That his serum contains immunoglobulins that react specifically with the epithelial cells of a normal subject. In both cases the specific auto-antibody is demonstrated by fluorescein-labelled antihuman IgG. Purely oral lesions in pemphigus may be adequately controlled by local steroids but systemic steroids are usually required, and this is the case when generalized disease occurs. Pemphigoid, as might be deduced from its title, may be clinically indistinguishable from pemphigus. The lesions are however subepithelial and tend to 'spread' less. The disease is one of the elderly and is common in females. Lesions tend to be oral and ocular, while they are sparse on the skin. Diagnosis may be effected by biopsy. The specific prickle cell autoantibodies of pemphigus are absent but there may be demonstrable antibody attached to the basement membrane of the epithelium. Treatment is with topical steroids. Erythema multiforme is a rather unusual condition. It is a clinical manifestation which may be produced by allergy to drugs or by infection with Mycoplasma pneumoniae but in most cases the cause cannot be demonstrated. The most severe cases are sometimes unnecessarily distinguished by the eponymous title Stevens-Johnson syndrome. There may be widespread visceral damage since the pathogenesis is in intravascular antigen-antibody reaction. The oral features are of widespread patchy inflammation; at sites of most intense reaction bullous formation occurs, thence ulceration. The lips are invariably involved and become coated by haemorrhagic exudate which is a characteristic feature. The skin is usually affected to a greater extent than oral mucosa. The cause should be established if possible by careful questioning for allergies. If Myco. pneumoniae appears to be the cause as revealed by typical pneumonia then tetracycline is indicated. Otherwise systemic steroids are the mainstay of treatment, with supportive therapy. Finally mention must be made of one of the rarest causes of bullous lesions of the oral mucosa, namely primary amyloidosis. Recurrent small blood-filled bullae occur due to minor trauma and these, although an unusual feature of this condition, are almost pathognomonic. They are useful since biopsy of them will provide diagnostic histopathological material. 103
R. Haskell The causes of oral ulceration are large and varied. The vesiculo-bullous lesions form a subgroup which can usually be distinguished clinically by their named characteristic. Equally each member of the group has distinctive clinical features which I hope this presentation has highlighted. Greenwich District Hospital, Vanbrugh Hill, London, SEio aHE.
104
