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Figure 1.
A 34-year-old woman presents to the emergency department (ED) with a 3-day history of pain around the right ear extending to the temple. She was sitting at work today when she suddenly experienced dizziness, a feeling of discomfort in the throat, and a burning sensation in the left arm and leg. When she tried to stand and walk, her right arm and leg did not move in a normal, coordinated manner. The patient was previously healthy and does not take any regular medications. She does not smoke or drink. She does vigorous aerobic exercises on an almost daily basis. Her mother and a number of relatives on her mother's side suffer from hypertension.
On physical examination, the patient has an oral temperature of 98.6°F (37.0°C). Her pulse is regular with a rate of 86 bpm. Her blood pressure is 164/90 mm Hg, and her heart sounds are normal and without added sounds. There are no arterial bruits auscultated in her neck. She is noted to have prolonged bouts of hiccuping. She is unable to stand due to a severe feeling of imbalance. There is right-sided ptosis and miosis. She has a sustained horizontal gaze-evoked nystagmus looking to the left and right, with a downbeating nystagmus on downward gaze. There is decreased sensation of pinprick and temperature on the right side of the face. On the right side there is also reduced movement of the palate, and the gag reflex is diminished. The tongue movements are normal. The power is normal in all 4 limbs, the deep tendon reflexes are normal, and the plantar responses are downgoing bilaterally (there is no Babinski sign). There is a moderate degree of ataxia affecting the right arm and leg. There is decreased sensation to pinprick and temperature on the left arm, leg, and trunk. The joint position and vibration sense are intact bilaterally.
Routine laboratory analysis, including a complete blood cell count, a basic metabolic panel, and a lipid profile, is normal. A noncontrast computed tomography (CT) scan of the head is normal. Magnetic resonance imaging (MRI) of the brain is obtained.The patient in this case was diagnosed with a lateral medullary stroke on the right with Wallenberg syndrome.
Neurons relaying pain and temperature sensation from the right side of the face synapse in the descending spinal nucleus of the trigeminal nerve, which lies in the dorsolateral aspect of the brainstem (Figure 2). Thereafter, the pathway crosses (as the quintothalamic tracts) and ascends to the thalamus. For the limbs and trunk, the neurons of the spinothalamic tract from the left side of the body pass into the spinal cord, where they ascend for 1 or 2 levels (via Lissauer's tract) and then synapse. The second-order neurons then cross to the right side of the spinal cord (via the anterior commissure, just anterior to the central canal of the cord) and then ascend in the anterolateral aspect of the spinal cord up into the right side of the brainstem. In the brainstem, the spinothalamic tract lies laterally.
This patient had impairment of pain and temperature (ie, spinothalamic) sensation on the right side of the face and the left side of the body. These contralateral findings are characteristic of a right lateral medullary lesion. The patient also had reduced palatal movements and gag reflex on the right side indicative of involvement of the right IX (glossopharyngeal) and X (vagus) cranial nerves. These cranial nerves, as well as the descending sympathetic fibers (patient had a right-sided Horner's sign), are also found in the dorsolateral aspect of the right side of the medulla (Figure 2). The presence of vertigo and right-sided ataxia was due to involvement of the vestibular nucleus and cerebellar pathways (as they pass into the cerebellum through the inferior cerebellar peduncle), respectively, on the right side. The nucleus and the fascicles of the hypoglossal nerve lie medially within the medulla, and the pyramidal pathways lie anteromedially as they pass through the medulla. The joint position and vibration sense modalities pass up the spinal cord on the ipsilateral side and then synapse at the gracile and cuneate nuclei in the lower part of the medulla. The dorsal column pathways then cross (as the internal arcuate fibres) at the level of the lower medulla and then pass up the medial aspect of the brainstem as the medial lemnisci. The normal tongue movements and the preserved pyramidal and dorsal column function in this patient indicate that there is sparing of the medial medulla; therefore, this patient had a right-sided lateral medullary syndrome (ie, Wallenberg syndrome), which was determined by brain MRI to be a stroke. The T2-weighted coronal scan shows a high signal abnormality in the right side of the medulla (black arrow, Figure 1).
The presence of prominent right ear pain for 3 days prior to developing neurologic deficits is suggestive of a vertebral artery dissection. In fact, stroke preceded by headache or neck pain should always raise suspicion for cervical arterial dissection. The patient performed vigorous aerobic exercises on an almost daily basis, and these exercises included repetitive high-energy lateral neck flexions. This is likely to have been the cause of an arterial dissection. The diagnosis made was of a dissection of the right vertebral artery and a subsequent infarction of the dorsolateral aspect of the right medulla.
The lateral medullary syndrome (also called Wallenberg or posterior inferior cerebellar artery [PICA] syndrome) was first described by Gaspard Vieusseux in 1808. Subsequent clinical (1895) and autopsy (1901) descriptions by Wallenberg led to the syndrome being associated with his name. The loss of pain and temperature sensation on the ipsilateral side of the face and contralateral side of the body is characteristic of this condition. Other clinical features include intractable hiccups, vertigo, Horner syndrome, nystagmus, dysarthria, dysphagia, and ipsilateral ataxia. The blood supply to the medulla is mainly from the vertebral arteries. At the level of the lower medulla, each vertebral artery gives off a variable branch named the posterior inferior cerebellar artery (which may be absent in up to 25% of the population) that supplies the dorsolateral aspects of the medulla. At a higher level, approaching the pontomedullary junction, each vertebral artery also contributes branches to form the anterior spinal artery, which descends over the anterior surface of the medulla and supplies the medial aspects of the medulla. The majority of cases of Wallenberg syndrome are therefore due to vascular events, whereby the dorsolateral aspect of the medulla may be involved, with sparing of the medial medulla due to an intact anterior spinal artery supply. Definitive pathologic[1] and more recent MRI[2] studies indicate that lateral medullary infarctions occur due to involvement of the vertebral artery in 38% of cases. PICA is involved 14%-24% of the time, and both arteries are involved in 26% of cases. No abnormality is found in either vessel only 12%-19% of the time.
Intravenous thrombolysis (IVT) is an acute treatment of the lateral medullary syndrome. Although still very controversial, some studies show that IVT using recombinant tissue plasminogen activator (tPA) is efficacious for acute ischemic stroke.[3] Dissection is not an absolute contraindication to IVT; however, if a vertebral artery dissection extends intracranially (which is uncommon), caution is advised due to an increased risk for bleeding. The ECASS 3 trial recently demonstrated benefit of IVT given up to 4.5 hours after symptom onset in ischemic stroke, although certain patients were excluded from this trial and this practice is not standard of care.[4] Newer, invasive stent-based techniques exist for stroke and dissection treatment, though they are available at very few centers. If a patient with a nonhemorrhagic stroke is seen beyond the time window for IVT, then aspirin may be given. In this case, because there was a vertebral artery dissection, anticoagulation with heparin and subsequently warfarin was indicated.
The mechanism of the intractable hiccups that is often observed in the lateral medullary syndrome is poorly understood. Occasionally, gabapentin or chlorpromazine is effective. Patients may experience disturbed vision due to persistent nystagmus, and this may be helped by gabapentin or memantine.[5]
Cervical artery dissections (CADs) may involve the carotid or vertebral arteries. They are implicated in 2% of all ischemic strokes but in up to 10%-25% of cases in young and middle-aged patients. CAD may occur spontaneously, and several inheritable connective tissue disorders (eg, Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal dominant polycystic kidney disease, and osteogenesis imperfecta) are associated with an increased risk. Familial arterial dissections have been associated with generalized lentiginosis, coarctation of the aorta, bicuspid aortic valve, and aortic root dilatation. Traumatic CAD occurs most frequently following motor vehicle accidents. Less violent forms of trauma have also been implicated in CAD, especially cervical spine chiropractic manipulations. Other forms of trauma implicated in CAD include contact sports, yoga, calisthenics, vigorous aerobic exercise, ceiling painting, tonic-clonic seizures, and riding on roller coasters. The mechanism of stroke in CAD is usually thromboembolic due to disruption of normal blood flow in the region of dissection. Less commonly, there may be partial or total occlusion of the vessel, which then results in low blood flow and watershed ischemia. The presence of a CAD may be confirmed by formal cerebral angiography, but less invasive procedures such as MR angiography, CT angiography, or duplex Doppler studies are diagnostic in a high proportion of patients.
The patient in this case presented acutely to the ED, had a normal CT head scan, and was within the time window to receive treatment with IVT. She was given 0.9 mg/kg of recombinant tPA intravenously 3 hours and 15 minutes after the onset of her stroke. She remained well, and 24 hours later she was started on oral aspirin therapy. Her intractable hiccups were treated with oral chlorpromazine and resolved after 2 weeks. Because she was experiencing an intrusive burning sensation affecting the left side of her body as well as disturbed vision due to persistent nystagmus, she was started on gabapentin therapy. Both of these symptoms were controlled well with gabapentin at 1800 mg per day. The patient's dysphagia and right-sided limb ataxia improved such that she was able to eat a normal diet and walk within 1 week of hospital admission. The patient was discharged to home and was able to return to her employment as an accountant 10 weeks after her stroke.You are seeing a patient in whom you suspect a brainstem stroke due to a vertebral artery dissection. Which of the following investigations is most appropriate after an initial noncontrast CT scan of the head?
MRI studies are considered the noninvasive imaging modality of choice in this situation. CT angiography is also acceptable but will not identify the stroke. The images obtained from the MRI scan of the head may directly detect the pathologic lesion. In the patient presented in the case, the T1-weighted and fluid-attenuated inversion recovery (FLAIR) sequences of the MRI showed a bright signal across the right vertebral artery wall. It also demonstrated the right lateral medullary infarction. These features are highly suggestive of fresh blood and/or recent thrombus throughout the vessel wall seen in arterial dissection. Conditions associated with an arterial dissection may be demonstrated by an echocardiogram and appropriate genetic testing (eg, for Marfan syndrome) but will not help in confirming the presence of an arterial dissection. A lumbar puncture has no role in stroke or dissection evaluation.
The patient described above is found to have a vertebral artery dissection and stroke with Wallenberg syndrome. Which symptom or sign would you expect to find in this patient?The loss of pain and temperature sensation on the ipsilateral side of the face and contralateral side of the body is characteristic of Wallenberg syndrome. Other clinical features include intractable hiccups, vertigo, Horner syndrome, nystagmus, dysarthria, dysphagia and ipsilateral ataxia.
Wednesday, November 10, 2010
Tuesday, November 9, 2010
BULLOUS PEMPHIGIOD
An 84-year-old woman presents with a blistering rash. The rash began 1 week ago on her right hand, but it has progressed to her arm, upper chest, and abdomen. The rash is painless but intensely itchy, and it limits her ability to complete routine tasks. She has had no fever, no history of trauma, and no recent travel. She lives alone and uses an electric scooter to assist her with mobility. The patient relies on help from family and caretakers for the activities of daily living. She has a medical history of 100% estrogen-receptor-positive nonmetastatic breast cancer, ischemic heart disease, osteoporosis, and chronic renal insufficiency. The patient takes aspirin, isosorbide mononitrate, ramipril, simvastatin alendronate, and a calcium supplement. Her breast cancer is treated with an aromatase inhibitor. She has had no recent changes in her medication regimen and does not take any over-the-counter or herbal medications.
On physical examination, the patient appears frail but nontoxic. Her temperature is 98.4°F (36.9°C). Her heart has a regular rhythm with a rate of 88 bpm. Her blood pressure is 146/88 mm Hg and her respiratory rate is timed at 16 breaths/min. She has clear, equal bilateral breath sounds. There are no heart murmurs, but a loud S2 heart sound is heard. Her apical impulse is not displaced. The patient's abdomen is soft and nontender, and no appreciable organomegaly is detected. She has a deep, fixed 3-cm mass underlying the nipple of her right breast, with overlying skin puckering. She does not have any axillary lymphadenopathy. Her current breast examination is unchanged from her last documented examination. Examination of the skin reveals several tense bullae, excoriated papules, and vesicles ranging in size from a few millimeters to 3 centimeters over her right arm, anterior chest, and abdomen (see Figures 1 and 2). These bullae and vesicles rest on an erythematous base, and they contain clear fluid. There is no involvement of the mucous membranes and the Nikolsky sign (blistering of healthy-appearing skin when it is rubbed) is not elicited.
Laboratory tests are performed, which demonstrate normal erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), and C-reactive protein (CRP) findings. She has a hemoglobin level of 12.7 g/dL (127 g/L), with a mild eosinophilia measured at 0.48 × 109/L. Her blood urea nitrogen is 28 mg/dL (10 mmol/L) and her creatinine level is 2.1 mg/dL (185.64 µmol/L). Her liver function tests are unremarkable.The patient in this case exhibited many factors suggestive of a diagnosis of bullous pemphigoid. Her advanced age, the clinical appearance of the skin lesions, and the subacute onset of an intensely pruritic, nonpainful rash were consistent with the diagnosis of bullous pemphigoid, and a skin biopsy sent for routine histology, direct immunofluorescence, and indirect immunofluorescence studies confirmed it. Histopathology of a subepidermal blister demonstrated an eosinophil-rich inflammatory infiltrate in the dermis. Viral and bacterial culture swabs from the blister fluid had a negative result, which excluded an infectious process (such as herpes zoster).
Bullous pemphigoid is the most common blistering autoimmune disorder in the Western world, with an estimated incidence of 6-7 cases per million in France and Germany, and an unknown incidence in the United States. It is a relatively benign condition that tends to run a waxing and waning course, with recurrent episodes of remission and relapse. It most commonly affects the elderly but can also rarely occur in younger patients and infants.[1,2,4] In cases of bullous pemphigoid, immunoglobulin G (IgG) autoantibodies attack the skin basement membrane zone, which induces an inflammatory response and activates the complement system. The 2 main antigenic targets that have been identified are known as bullous pemphigoid antigen 1 (BPAg1; a 230-kd protein) and bullous pemphigoid antigen 2 (BPAg2; a 180-kd protein). They are both components of the hemidesmosome and allow linkage of intermediate filaments to the basement membrane. Of these antigens, BPAg2 is thought to be the major contributor to the pathophysiology of bullous pemphigoid. Animal studies have shown failure of blistering to occur with antibodies induced solely against BPAg1.[2] In these cases, eosinophils are characteristically found on skin histopathology. They migrate to the area of injury by the activity of an eosinophil-specific chemokine called eotaxin.[2] Interleukin-16 (IL-16) is another cytokine that has been found in high concentrations in the serum of patients with bullous pemphigoid. IL-16 stimulates CD-4 helper cells and up-regulates interleukin-2 receptors.
Bullous pemphigoid can present acutely or subacutely with tense round or oval-shaped blisters and vesicles. Intensely itchy urticarial lesions can precede the bullae by days, weeks, or even months. The lesions of bullous pemphigoid may either be localized or generalized throughout the body, and they often affect the flexor areas of the limbs, as well as affecting the abdomen, chest, and medial thighs. Mucous membrane involvement may occur, but it is not common. The lesions heal without any scarring.[1,2] Although more commonly seen in pemphigus, the Nikolsky sign can also be occasionally seen in cases of pemphigoid. The Nikolsky sign is described as the separation of superficial skin from the deeper dermis with the application of gentle pressure.
A full history and physical examination is essential for recognizing the diagnosis and determining the etiology. Drug-induced bullous pemphigoid is well recognized and has many causes, including diuretics, antibiotics, and angiotensin-converting enzyme (ACE) inhibitors. Cessation of the drug normally prevents recurrence.[3] There is evidence of an association between bullous pemphigoid and malignancy; however, bullous pemphigoid itself has not been shown to increase the incidence of malignancy in age- and sex-matched controls.[1] Interestingly, Gül et al described a case of breast cancer with bone metastases presenting with bullous pemphigoid in a 62-year old-woman.[6] Bullous pemphigoid is a disease of the elderly and, of course, this population is much more prone to developing malignancy as well; therefore, a thorough examination for a possible associated malignancy is prudent.
The clinical differential diagnosis for bullous pemphigoid is broad and could include pemphigus vulgaris, linear immunoglobulin A (IgA) disease, epidermolysis bullosa acquisita, bullous lupus erythematosus, and dermatitis herpetiformis. Blistering rashes can also be seen with impetigo, acute viral infections, drug eruptions, and herpes zoster. The patient's history and physical examination will help narrow down this differential. The patient's age, vital signs, the distribution of the blisters, and the nature of the blister (ie, tense or flaccid) all provide clues; however, testing is ultimately necessary, including immunofluorescence studies, histopathology, and viral and bacterial swabs.[1,4] In bullous pemphigoid, indirect immunofluorescence using serum will demonstrate circulating antibodies to the basement membrane zone of human skin or monkey esophagus substrate in a linear pattern in 70% of patients.[2] Skin biopsy of a blister will often reveal an eosinophilic inflammatory infiltrate, whilst direct immunofluorescence of normal skin adjacent to the lesion will show linear deposits of IgG and C3 at the basement membrane zone.
Other variants of bullous pemphigoid include gestational pemphigoid and cicatricial pemphigoid. Gestational pemphigoid occurs during pregnancy and leads to bullae or urticarial lesions on the abdomen, trunk and extremities, with mucous membrane sparing. The fetus is not affected and the disease regresses after pregnancy, although it may reappear with future pregnancies. Cicatricial pemphigoid rarely involves the skin and tends to affect mucous membranes, with ocular and oropharyngeal involvement, and it can lead to scarring and significant morbidity from blindness and airway obstruction.[4]
The treatment options available for bullous pemphigoid include oral steroids or topical steroid creams, antibiotics, steroid-sparing immunosuppressants (such as azathioprine, mycophenolate mofetil, and methotrexate), plasmapheresis, and immunoglobulin infusions. Steroidal options include the use of high-potency topical steroids, and oral steroid therapy with prednisone 0.5-1mg/kg/day can be used as well. In patients with a high risk of osteoporosis, calcium and vitamin D supplements with a bisphosphonate should be considered.[2] For acutely ill patients or those with extensive skin involvement, fluid replacement, thermoregulation, and infection management may be necessary. Most patients with bullous pemphigoid are elderly; they may have multiple comorbidities and may be taking multiple medications. Treatment should be carefully tailored to minimize side effects yet allow for adequate disease control.
A systematic review by Khumalo et al found potent topical steroids were safe and effective in patients with bullous pemphigoid, with less systemic side effects than oral steroid treatment.[5] The side effects of steroid treatment can include diabetes mellitus, peptic ulcer disease, glaucoma, cataract formation, and agranulocytosis. The prognosis of patients with bullous pemphigoid is generally very good. Disease remission can vary from 1-5 years with treatment.
The patient in this case was treated with high-potency topical steroids and experienced a good result. The patient tapered the medication over a period of several weeks, and she regularly followed up with her health care provider.You are examining a patient and suspect that she is suffering from bullous pemphigoid. Which of the following findings is MOST likely to be found in this patient?
Tense blisters are most likely to be found in cases of bullous pemphigoid, and they may be either localized or generalized. The blisters may be preceded by urticarial plaques or pruritus, and they are most often seen in the flexor areas of the limbs, medial thighs, abdomen, groin, and chest wall. Mucosal involvement is uncommon. The lesions of bullous pemphigoid typically do not form scars. Pyrexia may be present if bullae are infected, but this is not typical. A dermatomal distribution would point to herpes zoster infection.
You are examining a 76-year-old patient who presented with a vesiculobullous rash on his elbows and knees that began 2 months ago. The rash is painful and limits his activities. His history reveals that he has experienced similar episodes in the past. You diagnose this patient with bullous pemphigoid, which is confirmed by histopathologic analysis and direct immunofluorescence testing. Which of the following choices would be the mainstay of treatment for this patient?While many treatment modalities exist, steroids are the mainstay of treatment. The treatment should be tailored to each individual patient, and it should account for any underlying medical conditions and medications taken.
On physical examination, the patient appears frail but nontoxic. Her temperature is 98.4°F (36.9°C). Her heart has a regular rhythm with a rate of 88 bpm. Her blood pressure is 146/88 mm Hg and her respiratory rate is timed at 16 breaths/min. She has clear, equal bilateral breath sounds. There are no heart murmurs, but a loud S2 heart sound is heard. Her apical impulse is not displaced. The patient's abdomen is soft and nontender, and no appreciable organomegaly is detected. She has a deep, fixed 3-cm mass underlying the nipple of her right breast, with overlying skin puckering. She does not have any axillary lymphadenopathy. Her current breast examination is unchanged from her last documented examination. Examination of the skin reveals several tense bullae, excoriated papules, and vesicles ranging in size from a few millimeters to 3 centimeters over her right arm, anterior chest, and abdomen (see Figures 1 and 2). These bullae and vesicles rest on an erythematous base, and they contain clear fluid. There is no involvement of the mucous membranes and the Nikolsky sign (blistering of healthy-appearing skin when it is rubbed) is not elicited.
Laboratory tests are performed, which demonstrate normal erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), and C-reactive protein (CRP) findings. She has a hemoglobin level of 12.7 g/dL (127 g/L), with a mild eosinophilia measured at 0.48 × 109/L. Her blood urea nitrogen is 28 mg/dL (10 mmol/L) and her creatinine level is 2.1 mg/dL (185.64 µmol/L). Her liver function tests are unremarkable.The patient in this case exhibited many factors suggestive of a diagnosis of bullous pemphigoid. Her advanced age, the clinical appearance of the skin lesions, and the subacute onset of an intensely pruritic, nonpainful rash were consistent with the diagnosis of bullous pemphigoid, and a skin biopsy sent for routine histology, direct immunofluorescence, and indirect immunofluorescence studies confirmed it. Histopathology of a subepidermal blister demonstrated an eosinophil-rich inflammatory infiltrate in the dermis. Viral and bacterial culture swabs from the blister fluid had a negative result, which excluded an infectious process (such as herpes zoster).
Bullous pemphigoid is the most common blistering autoimmune disorder in the Western world, with an estimated incidence of 6-7 cases per million in France and Germany, and an unknown incidence in the United States. It is a relatively benign condition that tends to run a waxing and waning course, with recurrent episodes of remission and relapse. It most commonly affects the elderly but can also rarely occur in younger patients and infants.[1,2,4] In cases of bullous pemphigoid, immunoglobulin G (IgG) autoantibodies attack the skin basement membrane zone, which induces an inflammatory response and activates the complement system. The 2 main antigenic targets that have been identified are known as bullous pemphigoid antigen 1 (BPAg1; a 230-kd protein) and bullous pemphigoid antigen 2 (BPAg2; a 180-kd protein). They are both components of the hemidesmosome and allow linkage of intermediate filaments to the basement membrane. Of these antigens, BPAg2 is thought to be the major contributor to the pathophysiology of bullous pemphigoid. Animal studies have shown failure of blistering to occur with antibodies induced solely against BPAg1.[2] In these cases, eosinophils are characteristically found on skin histopathology. They migrate to the area of injury by the activity of an eosinophil-specific chemokine called eotaxin.[2] Interleukin-16 (IL-16) is another cytokine that has been found in high concentrations in the serum of patients with bullous pemphigoid. IL-16 stimulates CD-4 helper cells and up-regulates interleukin-2 receptors.
Bullous pemphigoid can present acutely or subacutely with tense round or oval-shaped blisters and vesicles. Intensely itchy urticarial lesions can precede the bullae by days, weeks, or even months. The lesions of bullous pemphigoid may either be localized or generalized throughout the body, and they often affect the flexor areas of the limbs, as well as affecting the abdomen, chest, and medial thighs. Mucous membrane involvement may occur, but it is not common. The lesions heal without any scarring.[1,2] Although more commonly seen in pemphigus, the Nikolsky sign can also be occasionally seen in cases of pemphigoid. The Nikolsky sign is described as the separation of superficial skin from the deeper dermis with the application of gentle pressure.
A full history and physical examination is essential for recognizing the diagnosis and determining the etiology. Drug-induced bullous pemphigoid is well recognized and has many causes, including diuretics, antibiotics, and angiotensin-converting enzyme (ACE) inhibitors. Cessation of the drug normally prevents recurrence.[3] There is evidence of an association between bullous pemphigoid and malignancy; however, bullous pemphigoid itself has not been shown to increase the incidence of malignancy in age- and sex-matched controls.[1] Interestingly, Gül et al described a case of breast cancer with bone metastases presenting with bullous pemphigoid in a 62-year old-woman.[6] Bullous pemphigoid is a disease of the elderly and, of course, this population is much more prone to developing malignancy as well; therefore, a thorough examination for a possible associated malignancy is prudent.
The clinical differential diagnosis for bullous pemphigoid is broad and could include pemphigus vulgaris, linear immunoglobulin A (IgA) disease, epidermolysis bullosa acquisita, bullous lupus erythematosus, and dermatitis herpetiformis. Blistering rashes can also be seen with impetigo, acute viral infections, drug eruptions, and herpes zoster. The patient's history and physical examination will help narrow down this differential. The patient's age, vital signs, the distribution of the blisters, and the nature of the blister (ie, tense or flaccid) all provide clues; however, testing is ultimately necessary, including immunofluorescence studies, histopathology, and viral and bacterial swabs.[1,4] In bullous pemphigoid, indirect immunofluorescence using serum will demonstrate circulating antibodies to the basement membrane zone of human skin or monkey esophagus substrate in a linear pattern in 70% of patients.[2] Skin biopsy of a blister will often reveal an eosinophilic inflammatory infiltrate, whilst direct immunofluorescence of normal skin adjacent to the lesion will show linear deposits of IgG and C3 at the basement membrane zone.
Other variants of bullous pemphigoid include gestational pemphigoid and cicatricial pemphigoid. Gestational pemphigoid occurs during pregnancy and leads to bullae or urticarial lesions on the abdomen, trunk and extremities, with mucous membrane sparing. The fetus is not affected and the disease regresses after pregnancy, although it may reappear with future pregnancies. Cicatricial pemphigoid rarely involves the skin and tends to affect mucous membranes, with ocular and oropharyngeal involvement, and it can lead to scarring and significant morbidity from blindness and airway obstruction.[4]
The treatment options available for bullous pemphigoid include oral steroids or topical steroid creams, antibiotics, steroid-sparing immunosuppressants (such as azathioprine, mycophenolate mofetil, and methotrexate), plasmapheresis, and immunoglobulin infusions. Steroidal options include the use of high-potency topical steroids, and oral steroid therapy with prednisone 0.5-1mg/kg/day can be used as well. In patients with a high risk of osteoporosis, calcium and vitamin D supplements with a bisphosphonate should be considered.[2] For acutely ill patients or those with extensive skin involvement, fluid replacement, thermoregulation, and infection management may be necessary. Most patients with bullous pemphigoid are elderly; they may have multiple comorbidities and may be taking multiple medications. Treatment should be carefully tailored to minimize side effects yet allow for adequate disease control.
A systematic review by Khumalo et al found potent topical steroids were safe and effective in patients with bullous pemphigoid, with less systemic side effects than oral steroid treatment.[5] The side effects of steroid treatment can include diabetes mellitus, peptic ulcer disease, glaucoma, cataract formation, and agranulocytosis. The prognosis of patients with bullous pemphigoid is generally very good. Disease remission can vary from 1-5 years with treatment.
The patient in this case was treated with high-potency topical steroids and experienced a good result. The patient tapered the medication over a period of several weeks, and she regularly followed up with her health care provider.You are examining a patient and suspect that she is suffering from bullous pemphigoid. Which of the following findings is MOST likely to be found in this patient?
Tense blisters are most likely to be found in cases of bullous pemphigoid, and they may be either localized or generalized. The blisters may be preceded by urticarial plaques or pruritus, and they are most often seen in the flexor areas of the limbs, medial thighs, abdomen, groin, and chest wall. Mucosal involvement is uncommon. The lesions of bullous pemphigoid typically do not form scars. Pyrexia may be present if bullae are infected, but this is not typical. A dermatomal distribution would point to herpes zoster infection.
You are examining a 76-year-old patient who presented with a vesiculobullous rash on his elbows and knees that began 2 months ago. The rash is painful and limits his activities. His history reveals that he has experienced similar episodes in the past. You diagnose this patient with bullous pemphigoid, which is confirmed by histopathologic analysis and direct immunofluorescence testing. Which of the following choices would be the mainstay of treatment for this patient?While many treatment modalities exist, steroids are the mainstay of treatment. The treatment should be tailored to each individual patient, and it should account for any underlying medical conditions and medications taken.
DENGUE HEMORRHAGIC FEVER
A 45-year-old woman presents to the emergency department with bleeding gums and bruises on both forearms for the last 2 days. For the preceding 10 days she had been experiencing a high fever (which has since broken) and rigors. In addition, she complains of a rash over both forearms, but she is unable to further characterize it. She noted severe pain in both legs during the febrile portion of her illness. There was no history of hematuria, melena, cough, or hemoptysis. She is not taking any routine prescription medications or using over-the-counter products or supplements. She has no known drug allergies. She is married with 5 children and is currently unemployed. She does not smoke or drink alcohol and has no history of drug abuse. There is no travel history or any history of sick contacts. She is a resident of Pakistan.
On physical examination, she is alert and apparently well developed and well nourished. The patient has a regular pulse of 90 bpm and a respiratory rate of 14 breaths/min. Her temperature is 98.2° F (36.8° C) and blood pressure is 110/70 mm Hg. The cardiac examination reveals a normal S1 and S2, with no murmur, gallop, or rub. Auscultation of the lungs is normal, and no palpable organomegaly or tenderness is found on abdominal examination. Examination of the extremities reveals large bruises and a petechial rash across both forearms and lower extremities (Figure 1; the image shown is an example of the rash seen). Conjunctival hemorrhages are noted bilaterally. Bruises are also apparent on her soft palate, and minor trauma from oral examination results in gingival hemorrhage.
The laboratory investigation reveals a hemoglobin of 8 g/dL (80 g/L), platelet count of 11 × 103/µL (11 × 109/L), and a white blood cell count of 1.8 × 103/µL (1.8 × 109/L). Her serum blood urea nitrogen, creatinine, liver function tests, albumin, and electrolytes are normal. Coagulation studies, including a prothrombin time, activated partial thromboplastin time, fibrin degradation products, and serum fibrinogen, are normal. Blood cultures do not show any growth. Urine analysis and urine culture result negative. Posteroanterior and lateral chest radiographs, as well as abdominal ultrasonography, are unrevealing.
(Enlarge Image)
Figure 1.
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Figure 1.
This patient was diagnosed with dengue hemorrhagic fever (DHF), which is a complication of dengue fever (DF). The diagnosis was eventually confirmed by paired immunoglobulin M samples demonstrating an acute rise in antibodies.
Dengue virus belongs to the family Flaviviridae (genus Flavivirus) and has emerged as the most common arboviral disease in the world. The disease is endemic to tropical and subtropical areas of the world, with about 2.5 billion people (40% of the world's population) at risk of acquiring the infection.[1] Dengue virus is transmitted to humans through the bites of infective female Aedes mosquitoes (particularly A aegypti and A albopictus). Mosquitoes generally acquire the virus while feeding on the blood of an infected person. After an incubation period of 8-10 days, an infected mosquito is capable, during probing and blood feeding, of transmitting the virus to susceptible individuals for the rest of its life.[2] Unlike malaria, which is more prevalent in rural areas, DF is spread via mosquitoes that thrive in highly populated urban environments.[3]
Four distinct, but closely related, viruses (termed dengue virus types 1-4 [DENV 1-4]) cause DF. Humans are the main amplifying host of the virus.[4] Infection with 1 of the 4 serotypes of dengue virus causes a wide spectrum of clinical disease, including asymptomatic infection, undifferentiated fever, DF, and DHF. DHF occurs in a minority of patients and is characterized by bleeding and plasma leakage, which may lead to shock.[5] The major risk factor for DHF is prior immunity to a single dengue virus serotype. Infection with one dengue serotype confers lifelong homotypic immunity and a very brief period of partial heterotypic immunity (~6 months), but an individual can eventually be infected by more than one serotype. An individual could therefore experience a case of DENV-1 fever in one year, followed by a case of DENV-2 fever in the following year. Third infections are, however, very rare, and fourth infections have never been reported.[6] Several serotypes can be in circulation during a particular epidemic.[7]
Some people infected with DF are asymptomatic. Young children often have a fever with a rash, but other symptoms are minor. Older children and adults may also have mild symptoms; however, they are more likely to experience classic DF.[2] Symptoms of DF include a high fever (up to 105° F [40.5° C]), severe headache, retro-orbital pain, severe muscle and joint pain, swollen lymph nodes, general malaise, nausea, and vomiting; a macular erythematous rash with petechiae may also be observed.[7] The differential diagnosis for DF and DHF is broad and includes meningococcal meningitis, septicemia and disseminated intravascular coagulation, other hemorrhagic fevers (Crimean Congo hemorrhagic fever, Ebola, etc.), thrombotic thrombocytopenic purpura, falciparum malaria, leptospirosis, aplastic anemia, acute leukemia, and yellow fever.
Direct person-to-person transmission of dengue virus has not been documented. A few case reports have been published of transmission of DENV through exposure to dengue-infected blood, organs, or other tissues from blood transfusions; solid organ or bone marrow transplants; needle stick injuries; and mucous membrane contact with dengue-infected blood.[8]
Dengue or dengue-like epidemics were reported throughout the nineteenth and early twentieth centuries in America, Southern Europe, North Africa, the east Mediterranean, Asia, Australia, and on various islands in the Indian Ocean, the south and Central Pacific, and the Caribbean. DHF has increased both in incidence and distribution over the past 40 years, and, in 1996, 2.5-3.0 billion people lived in areas potentially at risk for dengue virus transmission. It is estimated that there are 20 million cases of dengue infection annually, resulting in around 24,000 deaths.[9] The geographic distribution of dengue viruses and their mosquito vectors has expanded, and DHF has emerged in the Pacific region and the Americas. In Southeast Asia, epidemic DHF first appeared in the 1950s, but by 1975 it had become a leading cause of hospitalization and death among children in many countries in that region.[10] In Europe, the last dengue epidemic dates from 1927-1928 in Greece, with high mortality. However, there continues to be imported cases of DF in travelers returning to Europe from endemic areas.[11]
In the 1980s, DHF began a second expansion into Asia when Sri Lanka, India, and the Maldives Islands had their first major DHF epidemics; Pakistan first reported an epidemic of DF in 1994. The recent epidemics in Sri Lanka and India were associated with multiple dengue virus serotypes. After an absence of 35 years, epidemic DF occurred in both Taiwan and the People's Republic of China in the 1980s. The People's Republic of China had a series of epidemics caused by all 4 serotypes, and its first major epidemic of DHF, caused by DENV-2, was reported on Hainan Island in 1985. Singapore also had a resurgence of DF/DHF from 1990 to 1994 after a successful control program had prevented significant transmission for over 20 years. In other countries in Asia where DHF is endemic, the epidemics have become progressively larger in the last 15 years.[10]
A recent outbreak of DF in Karachi occurred in 2005 when Aga Khan University reported 30 positive cases out of 100. A recent trend of DF in southeastern countries is that it has become endemic, causing cyclical epidemics every 2-3 years.[12]
A major challenge for public health officials in all tropical areas of the world is the development and implementation of sustainable prevention and control programs that will reverse the trend of emergent DHF.[13] Environmental controls, including solid waste management, decreasing vector breeding sites by eliminating standing water, improvement in public awareness by media, and the use of household insecticides and mosquito repellants can help prevent the spread of dengue virus. Active case surveillance is important for early detection and implementation of control programs in the setting of acute epidemics.[11] Unfortunately, there is no commercially available vaccine to prevent dengue.[14] Tetravalent vaccines are currently being studied.
Clinically, the diagnosis of DF is suggested by the presence of fever, severe headache, maculopapular skin rash, and myalgias associated with either the isolation or identification of DENV from either serum, plasma, or tissue specimens, or by demonstration of a 4-fold increase of DENV antibodies in paired serum samples. The diagnosis of DHF is based on similar clinical features associated with a bleeding diathesis and/or thrombocytopenia. In some patients, a shock syndrome (dengue shock syndrome) may be observed.
The treatment of DF and DHF is essentially supportive. Antipyretics as well as fluid resuscitation, monitoring, and support are often necessary. Monitoring of laboratory parameters and replenishment with blood products as necessary are indicated in severe cases of DHF. The World Health Organization has created a useful guide (Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control; available at the WHO Website[9]) that delineates recommended approaches to the identification and management of DHF patients.
The patient presented in this case was admitted to an inpatient medical ward for 10 days and managed with intravenous fluids as well as repeated platelet and packed red blood cell transfusions. She was discharged when her platelet count reached 60 × 103/µL (60 × 109/L). She returned to the outpatient department after 3 weeks for follow-up, at which time her bleeding, rash, and other symptoms had improved.You are examining 30-year-old man who presents with increased bruising following a short bout of febrile illness accompanied by severe headaches, a rash, and muscle pain. You suspect dengue hemorrhagic fever (DHF). Which of the following situations puts this patient at greatest risk of developing DHF?
Dengue fever is an acute, mosquito-transmitted viral disease caused by any 1 of 4 virus serotypes (DENV-1-4). Infection with any of these causes a wide spectrum of clinical disease, ranging from asymptomatic infection, undifferentiated fever, and dengue fever (DF) to dengue hemorrhagic fever (DHF). Infection with one dengue serotype confers lifelong homotypic immunity and a very brief period of partial heterotypic immunity, but each individual can eventually be infected by more than one serotype. It is thought that subsequent infections with different serotypes in individuals put patients at risk for more severe manifestations of disease, including DHF. This is thought to be due to partial immunity, which may cause an amplification rather than a mediation of illness. Ebola is one of the many diseases in the differential diagnosis of dengue fever. Visiting an area with an active Ebola outbreak should raise suspicion for Ebola.
The diagnosis of DHF is confirmed with paired immunoglobulin M samples in the patient above. What is the most appropriate treatment plan for this patient?The treatment of DF and DHF is essentially supportive. Antipyretics as well as fluid resuscitation, monitoring, and support are often necessary. Monitoring of laboratory parameters and replenishment with blood products are indicated as necessary in severe cases of DHF. Antibiotics and EGDT are indicated for patients with significant bacterial infections and should likely be started empirically for severely ill, undifferentiated patients. However, they do not have a role in confirmed DHF. Plasmapheresis is indicated for treating thrombotic thrombocytopenic purpura, an illness in the differential diagnosis of dengue fever. Acyclovir is a treatment for herpes virus but is not indicated for DF.
On physical examination, she is alert and apparently well developed and well nourished. The patient has a regular pulse of 90 bpm and a respiratory rate of 14 breaths/min. Her temperature is 98.2° F (36.8° C) and blood pressure is 110/70 mm Hg. The cardiac examination reveals a normal S1 and S2, with no murmur, gallop, or rub. Auscultation of the lungs is normal, and no palpable organomegaly or tenderness is found on abdominal examination. Examination of the extremities reveals large bruises and a petechial rash across both forearms and lower extremities (Figure 1; the image shown is an example of the rash seen). Conjunctival hemorrhages are noted bilaterally. Bruises are also apparent on her soft palate, and minor trauma from oral examination results in gingival hemorrhage.
The laboratory investigation reveals a hemoglobin of 8 g/dL (80 g/L), platelet count of 11 × 103/µL (11 × 109/L), and a white blood cell count of 1.8 × 103/µL (1.8 × 109/L). Her serum blood urea nitrogen, creatinine, liver function tests, albumin, and electrolytes are normal. Coagulation studies, including a prothrombin time, activated partial thromboplastin time, fibrin degradation products, and serum fibrinogen, are normal. Blood cultures do not show any growth. Urine analysis and urine culture result negative. Posteroanterior and lateral chest radiographs, as well as abdominal ultrasonography, are unrevealing.
(Enlarge Image)
Figure 1.
[ CLOSE WINDOW ]
Figure 1.
This patient was diagnosed with dengue hemorrhagic fever (DHF), which is a complication of dengue fever (DF). The diagnosis was eventually confirmed by paired immunoglobulin M samples demonstrating an acute rise in antibodies.
Dengue virus belongs to the family Flaviviridae (genus Flavivirus) and has emerged as the most common arboviral disease in the world. The disease is endemic to tropical and subtropical areas of the world, with about 2.5 billion people (40% of the world's population) at risk of acquiring the infection.[1] Dengue virus is transmitted to humans through the bites of infective female Aedes mosquitoes (particularly A aegypti and A albopictus). Mosquitoes generally acquire the virus while feeding on the blood of an infected person. After an incubation period of 8-10 days, an infected mosquito is capable, during probing and blood feeding, of transmitting the virus to susceptible individuals for the rest of its life.[2] Unlike malaria, which is more prevalent in rural areas, DF is spread via mosquitoes that thrive in highly populated urban environments.[3]
Four distinct, but closely related, viruses (termed dengue virus types 1-4 [DENV 1-4]) cause DF. Humans are the main amplifying host of the virus.[4] Infection with 1 of the 4 serotypes of dengue virus causes a wide spectrum of clinical disease, including asymptomatic infection, undifferentiated fever, DF, and DHF. DHF occurs in a minority of patients and is characterized by bleeding and plasma leakage, which may lead to shock.[5] The major risk factor for DHF is prior immunity to a single dengue virus serotype. Infection with one dengue serotype confers lifelong homotypic immunity and a very brief period of partial heterotypic immunity (~6 months), but an individual can eventually be infected by more than one serotype. An individual could therefore experience a case of DENV-1 fever in one year, followed by a case of DENV-2 fever in the following year. Third infections are, however, very rare, and fourth infections have never been reported.[6] Several serotypes can be in circulation during a particular epidemic.[7]
Some people infected with DF are asymptomatic. Young children often have a fever with a rash, but other symptoms are minor. Older children and adults may also have mild symptoms; however, they are more likely to experience classic DF.[2] Symptoms of DF include a high fever (up to 105° F [40.5° C]), severe headache, retro-orbital pain, severe muscle and joint pain, swollen lymph nodes, general malaise, nausea, and vomiting; a macular erythematous rash with petechiae may also be observed.[7] The differential diagnosis for DF and DHF is broad and includes meningococcal meningitis, septicemia and disseminated intravascular coagulation, other hemorrhagic fevers (Crimean Congo hemorrhagic fever, Ebola, etc.), thrombotic thrombocytopenic purpura, falciparum malaria, leptospirosis, aplastic anemia, acute leukemia, and yellow fever.
Direct person-to-person transmission of dengue virus has not been documented. A few case reports have been published of transmission of DENV through exposure to dengue-infected blood, organs, or other tissues from blood transfusions; solid organ or bone marrow transplants; needle stick injuries; and mucous membrane contact with dengue-infected blood.[8]
Dengue or dengue-like epidemics were reported throughout the nineteenth and early twentieth centuries in America, Southern Europe, North Africa, the east Mediterranean, Asia, Australia, and on various islands in the Indian Ocean, the south and Central Pacific, and the Caribbean. DHF has increased both in incidence and distribution over the past 40 years, and, in 1996, 2.5-3.0 billion people lived in areas potentially at risk for dengue virus transmission. It is estimated that there are 20 million cases of dengue infection annually, resulting in around 24,000 deaths.[9] The geographic distribution of dengue viruses and their mosquito vectors has expanded, and DHF has emerged in the Pacific region and the Americas. In Southeast Asia, epidemic DHF first appeared in the 1950s, but by 1975 it had become a leading cause of hospitalization and death among children in many countries in that region.[10] In Europe, the last dengue epidemic dates from 1927-1928 in Greece, with high mortality. However, there continues to be imported cases of DF in travelers returning to Europe from endemic areas.[11]
In the 1980s, DHF began a second expansion into Asia when Sri Lanka, India, and the Maldives Islands had their first major DHF epidemics; Pakistan first reported an epidemic of DF in 1994. The recent epidemics in Sri Lanka and India were associated with multiple dengue virus serotypes. After an absence of 35 years, epidemic DF occurred in both Taiwan and the People's Republic of China in the 1980s. The People's Republic of China had a series of epidemics caused by all 4 serotypes, and its first major epidemic of DHF, caused by DENV-2, was reported on Hainan Island in 1985. Singapore also had a resurgence of DF/DHF from 1990 to 1994 after a successful control program had prevented significant transmission for over 20 years. In other countries in Asia where DHF is endemic, the epidemics have become progressively larger in the last 15 years.[10]
A recent outbreak of DF in Karachi occurred in 2005 when Aga Khan University reported 30 positive cases out of 100. A recent trend of DF in southeastern countries is that it has become endemic, causing cyclical epidemics every 2-3 years.[12]
A major challenge for public health officials in all tropical areas of the world is the development and implementation of sustainable prevention and control programs that will reverse the trend of emergent DHF.[13] Environmental controls, including solid waste management, decreasing vector breeding sites by eliminating standing water, improvement in public awareness by media, and the use of household insecticides and mosquito repellants can help prevent the spread of dengue virus. Active case surveillance is important for early detection and implementation of control programs in the setting of acute epidemics.[11] Unfortunately, there is no commercially available vaccine to prevent dengue.[14] Tetravalent vaccines are currently being studied.
Clinically, the diagnosis of DF is suggested by the presence of fever, severe headache, maculopapular skin rash, and myalgias associated with either the isolation or identification of DENV from either serum, plasma, or tissue specimens, or by demonstration of a 4-fold increase of DENV antibodies in paired serum samples. The diagnosis of DHF is based on similar clinical features associated with a bleeding diathesis and/or thrombocytopenia. In some patients, a shock syndrome (dengue shock syndrome) may be observed.
The treatment of DF and DHF is essentially supportive. Antipyretics as well as fluid resuscitation, monitoring, and support are often necessary. Monitoring of laboratory parameters and replenishment with blood products as necessary are indicated in severe cases of DHF. The World Health Organization has created a useful guide (Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control; available at the WHO Website[9]) that delineates recommended approaches to the identification and management of DHF patients.
The patient presented in this case was admitted to an inpatient medical ward for 10 days and managed with intravenous fluids as well as repeated platelet and packed red blood cell transfusions. She was discharged when her platelet count reached 60 × 103/µL (60 × 109/L). She returned to the outpatient department after 3 weeks for follow-up, at which time her bleeding, rash, and other symptoms had improved.You are examining 30-year-old man who presents with increased bruising following a short bout of febrile illness accompanied by severe headaches, a rash, and muscle pain. You suspect dengue hemorrhagic fever (DHF). Which of the following situations puts this patient at greatest risk of developing DHF?
Dengue fever is an acute, mosquito-transmitted viral disease caused by any 1 of 4 virus serotypes (DENV-1-4). Infection with any of these causes a wide spectrum of clinical disease, ranging from asymptomatic infection, undifferentiated fever, and dengue fever (DF) to dengue hemorrhagic fever (DHF). Infection with one dengue serotype confers lifelong homotypic immunity and a very brief period of partial heterotypic immunity, but each individual can eventually be infected by more than one serotype. It is thought that subsequent infections with different serotypes in individuals put patients at risk for more severe manifestations of disease, including DHF. This is thought to be due to partial immunity, which may cause an amplification rather than a mediation of illness. Ebola is one of the many diseases in the differential diagnosis of dengue fever. Visiting an area with an active Ebola outbreak should raise suspicion for Ebola.
The diagnosis of DHF is confirmed with paired immunoglobulin M samples in the patient above. What is the most appropriate treatment plan for this patient?The treatment of DF and DHF is essentially supportive. Antipyretics as well as fluid resuscitation, monitoring, and support are often necessary. Monitoring of laboratory parameters and replenishment with blood products are indicated as necessary in severe cases of DHF. Antibiotics and EGDT are indicated for patients with significant bacterial infections and should likely be started empirically for severely ill, undifferentiated patients. However, they do not have a role in confirmed DHF. Plasmapheresis is indicated for treating thrombotic thrombocytopenic purpura, an illness in the differential diagnosis of dengue fever. Acyclovir is a treatment for herpes virus but is not indicated for DF.
Monday, November 1, 2010
recurrent urinary tract infection
A 28 year presents to your office with symptoms of a urinary tract infetion. This is her second infection in two months. You treated the last infection with Bactrim DS for 3 days. Her symptoms never really improved. Now she has worsening lower abdominal discomfort, dysuria & frequency. She has ha no fever or flank pain. Physical examination shows only mild suprapubic tenderness.
Approximately 15-20% of women develop recurrent UTI at some stage during their life. Cystitis is diagnosed when a clean-catch urine sample has a concentration of at least 1,00,000 bacteria /ml of urine & when the patient suffers the symptoms of dysuria, frequency , urgency & pain. The most common etiology of UTI is e-coli. Treatment of a UTI involves obtaining a culture & staring a patient on an antibiotic regimen of sulfa or nitrofurantoin, which have good coverage against e-coli & are relatively inexpensive.
Approximately 15-20% of women develop recurrent UTI at some stage during their life. Cystitis is diagnosed when a clean-catch urine sample has a concentration of at least 1,00,000 bacteria /ml of urine & when the patient suffers the symptoms of dysuria, frequency , urgency & pain. The most common etiology of UTI is e-coli. Treatment of a UTI involves obtaining a culture & staring a patient on an antibiotic regimen of sulfa or nitrofurantoin, which have good coverage against e-coli & are relatively inexpensive.
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