domingo, 29 de agosto de 2010
Para estudantes de Medicina
Caso clinico - New England Journal of Medicina
Toda história abaixo
Presentation of Case
Dr. Joseph D. Tucker (Infectious Diseases): A 54-year-old man was admitted to because of acute unilateral loss of vision.
On the morning before admission, the patient noted decreased central vision in his left eye. That evening after work, he went to an ophthalmologist. He reported that peripheral vision in the left eye and vision in the right eye were normal; he did not have headache, eye or neck pain, flashes of light, or other visual symptoms. On examination, visual acuity in the left eye was 20/400. Funduscopic examination of the left eye after dilatation revealed a pale, edematous optic nerve, with fine vessels on the surface, and flame-shaped hemorrhages inferior to the nerve. The erythrocyte sedimentation rate was reportedly elevated. He was referred to a neurologist, who sent him to the emergency department at this hospital, where he arrived approximately 31 hours after the onset of symptoms.
A diagnosis of stage IIB Hodgkin's lymphoma had been made 10 months before this admission; the presenting symptoms were cervical and mediastinal lymphadenopathy, drenching night sweats, and pruritus. Treatment included chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine followed by mechlorethamine, procarbazine, and prednisone), which was completed 4 months before admission, followed by radiation therapy (a total of 21 Gy in 12 fractions to cervical and mediastinal lymph nodes), which was completed 1 month before admission. Symptoms resolved after the first cycle of chemotherapy, and repeat imaging studies at the completion of chemotherapy showed resolution of the lymphadenopathy. Chemotherapy was complicated by persistent pancytopenia and recurrent infections (which persisted after completion of chemotherapy), for which transfusions, growth factors, and antibiotics were administered, and peripheral neuropathy, with numbness and paresthesias in the hands and feet and decreased sensation of pinprick and vibration on examination.
Five months before admission, a macular rash developed on the trunk, associated with low-grade fevers, thought to represent filgrastim-associated neutrophilic dermatitis. Two months before admission, two episodes of vertigo occurred, associated with nausea, vomiting, and unsteady gait. Meclizine was administered, with partial improvement but some persistent unsteadiness. The patient had lost 20 kg since the diagnosis of lymphoma.
A diagnosis of the Guillain–Barré syndrome had been made 10 years earlier; it was manifested by progressive sensory loss and diminished reflexes, without weakness. Testing for the human immunodeficiency virus (HIV) was negative at that time. Immune globulin was administered intravenously, and the symptoms resolved within 6 months. The patient also had chronic back pain, with compression fractures of the 11th and 12th thoracic vertebrae and cervical degenerative disk disease. He had had an appendectomy, shoulder arthroscopy, and a fractured leg in the past. Medications on admission included citalopram, lorazepam, antiinflammatory medications, and meclizine. He lived in New England, was married, was monogamous with his wife, and worked in an office. He drank alcohol occasionally, had stopped smoking years earlier, and did not use illicit drugs. His father had cardiovascular disease, diabetes mellitus, and stroke; his mother had arthritis; and his siblings were healthy.
On examination, the temperature was 36.3°C, the blood pressure 90/55 mm Hg, the pulse 71 beats per minute, the respiratory rate 20 breaths per minute, and the oxygen saturation 100% while the patient was breathing ambient air. There was no pain in the scalp or over temporal areas. Corrected visual acuity was 20/20 in the right eye and 20/200 in the left eye, with effort and eccentric fixation. Visual-field testing revealed a dense central scotoma and diminished color vision. The pupils contracted symmetrically on illumination. There was a relative afferent pupillary defect in the left eye. Eye movements were normal. The globes were normal to touch, were not tender, and had no proptosis. The left upper eyelid had mild ptosis from dermal redundancy. The conjunctivae were normal. Percussion of the frontal and maxillary sinuses did not elicit pain. On funduscopic examination, the right optic nerve was normal. The left optic nerve was diffusely edematous, with small splinter hemorrhages at the 6 and 7 o'clock positions. No Roth spots or retinal hemorrhages were noted. The peripheral retinal vessels appeared normal. Pinprick sensation was decreased in the fingertips and toes. The gait was narrow-based and unsteady, and the patient was unable to perform tandem gait or to walk on his heels or toes. He swayed but did not fall on performance of a Romberg test. An erythematous, dry, flaking, patchy rash was present on the forehead, chest, and upper back. The remainder of the physical examination was normal.
Levels of serum electrolytes, calcium, phosphorus, and magnesium and tests of renal function were normal, and tests for cardiac ischemia were negative; other laboratory results are shown in Table 1. On magnetic resonance imaging (MRI) after the administration of gadolinium, computed tomography (CT), and CT angiography of the head and neck, the patient's ventricles, sulci, and cisterns were prominent relative to his age. The imaging scans also showed mild parenchymal volume loss; they were otherwise normal. The patient was admitted to this hospital.
Table 1 (não adicionada)
Methylprednisolone (1 g) was administered intravenously, with improvement in visual acuity to 20/100 in the left eye. Otolaryngologic examination was normal. A radiograph of the chest was normal. Results of laboratory tests are shown in Table 1. One unit of packed red cells and 2 units of fresh-frozen plasma were transfused.
On the third day, a lumbar puncture showed an opening pressure of 21 cm of water while the patient's legs were extended. Flow cytometry of the cerebrospinal fluid showed normal B cells and T cells; other results are shown in Table 2. On questioning by an infectious-diseases consultant, the patient recalled that 6 months before admission, an ulcer had developed on the dorsum of the penis, which was intermittently painful and which was thought to be a herpetic lesion. Topical powder was prescribed, and the lesion gradually resolved.
Table 2 (Não adicionada)
Cerebrospinal Fluid Analysis.
On the fourth day, at 8 a.m., the serum cortisol level was 2.7 ?g per deciliter (74 nmol per liter) (reference range between 8 a.m. and noon, 5 to 25 ?g per deciliter [138 to 690 nmol per liter]), and the thyrotropin level was normal. A dermatologist noted papules (erythematous to pink) and plaques with adherent scales on the scalp, the sides of the neck, the arms, the chest, and the upper back, distributed predominantly in areas of sun exposure.
A test result was received, and a diagnostic procedure was performed.
Dr. Misha L. Pless: May we review the imaging studies?
Dr. Bradley R. Buchbinder: The imaging studies were originally interpreted as normal. However, on review, there are two subtle findings. First, a CT scan shows elevation of the left optic-nerve head, reflecting the edema observed on funduscopic examination (Figure 1A and 1B). Second, a T2-weighted MRI scan suggests subtle enlargement and T2-weighted hyperintensity within the orbital segment of the left optic nerve (Figure 1C and 1D). There is no associated retrobulbar inflammation or abnormal gadolinium enhancement. The retrobulbar fat, extraocular muscles, paranasal sinuses, bones, brain, and visualized upper neck are normal. No enlarged cervical lymph nodes were visualized.
Dr. Pless: I am aware of the diagnosis in this case. Sudden monocular loss of central vision suggests a disorder of the optic nerve or retina. Although the neuro-ophthalmic examination is critical for confirmation of localization, the historical features are often useful in determining the final diagnosis. This patient either suddenly had a loss of vision or suddenly became aware of a previously existing loss of vision, a common phenomenon when visual loss is painless. This history alone suggests vascular occlusive or embolic causes of vision loss. The fact that the optic nerve was swollen at the onset of the vision loss not only helps to localize the process but also suggests involvement of the central nervous system. The features of the optic nerve — that it was pale, swollen, and segmentally hemorrhagic — are consistent with vascular occlusion of the optic-nerve circulation, but pallor could also indicate an acute-on-chronic process.
Anterior Ischemic Optic Neuropathy
Anterior ischemic optic neuropathy, caused by occlusion of the posterior ciliary arteries, is an important consideration in this case.1–3 This condition tends to occur in patients who have hypertension and diabetes, but the absence of these disorders does not rule out the diagnosis.2,3 Severe anemia, present in this patient, is one of the rare causes of anterior ischemic optic neuropathy.1 The high erythrocyte sedimentation rate raises the possibility of vasculitis, such as giant-cell arteritis, as a cause of optic-nerve infarction.4 Failure to recognize and treat giant-cell arteritis promptly can lead to further worsening of vision in the affected eye, loss of vision in the other eye, and stroke. Unless an alternative cause is quickly established, a temporal-artery biopsy is mandatory, despite temporal arteries that are normal to the touch. A temporal-artery biopsy was planned for this patient.5
Since this patient had a history of Hodgkin's lymphoma, could his optic neuropathy be caused by either lymphoma or its treatment? Hodgkin's lymphoma rarely involves the orbit, eye, or central nervous system, but cases of Hodgkin's lymphoma involving the orbit or optic nerve at either presentation or relapse have been reported.6–9 This patient's systemic lymphoma responded well to chemotherapy and appears to be in remission, but ocular or central nervous system relapses may occur during or shortly after remission of systemic lymphoma.8 However, although Hodgkin's lymphoma could be the cause of the patient's acute optic neuropathy, the lack of intense gadolinium enhancement in the MRI scan of the optic nerve makes this diagnosis less likely.
This patient has peripheral neuropathy, which is in part residual from the Guillain–Barré syndrome but is also a common complication of vincristine and vinblastine therapy. Optic neuritis due to vincristine therapy has been reported, but it is typically bilateral and would be unlikely to develop so long after the completion of therapy.10–12
Invasive Fungal Sinusitis
Infection is a primary concern in this patient who has unilateral optic neuropathy — in particular, opportunistic infections, in view of his history of chemotherapy and prolonged myelosuppression. The most important fungal organisms to consider are mucor and aspergillus. Optic neuropathy may be the sentinel sign of cranio-orbital mucormycosis, a syndrome associated with high morbidity and mortality.13,14 Typically, however, patients with invasive fungal sinusitis have pain and periorbital skin discoloration, as well as necrosis in the paranasal sinuses adjacent to the orbit and cavernous sinus. Optic-nerve involvement would seldom occur in the absence of an imaging abnormality in the region of the sinus or orbit. An absence of orbital or hemicranial pain, a lack of involvement of the orbital apex and cavernous sinus, intact periorbital osseous structures, imaging studies that do not show features of inflammation or invasion of the paranasal sinus, and a normal fiberoptic endoscopic examination by an otolaryngologist strongly argue against fungal infection as the cause of this patient's optic neuropathy.
Disorders Involving the Genitalia, Skin, and Eyes
Is the presence of a genital ulcer and a subsequent rash that occurred during chemotherapy a clue to the diagnosis? The patient's immunosuppressed state could have predisposed him to a herpetic eruption on the penis; this was the suspected diagnosis at the time. Herpes simplex virus (HSV) can cause optic neuritis and visual loss as part of the acute retinal necrosis syndrome.15,16 However, we would have to postulate that the skin eruption was unrelated to the genital and ocular problems. In addition, HSV-associated optic neuritis is typically accompanied by pain and other signs of inflammation.
Sarcoidosis may affect both the skin and the optic nerve, and the possibility of this diagnosis should not be overlooked.4 Sarcoidosis and Hodgkin's lymphoma may coexist, but it would be unexpected for sarcoidosis to become manifest during chemotherapy, when the patient has the most severe immunosuppression. Optic-nerve sarcoidosis would typically present with intense inflammation of the optic-nerve sheath on MRI, which was not the case in this patient.17
Behçet's disease may involve the skin of the genitalia, the eyes, and the central nervous system18; however, several features of this patient's case make this diagnosis unlikely. First, anterior and posterior uveitis and occlusion of the central retinal vein are hallmarks of ocular Behçet's disease. Also, the patient did not have oral ulcers, and the MRI scan of the brain did not show lesions suggestive of perivenular inflammation. Finally, it is unusual for the first manifestation of an autoimmune disorder to appear in a patient who is profoundly immunosuppressed owing to chemotherapy.
Although the patient reported being monogamous, infection with Treponema pallidum best fits the sequence of events that culminated in optic neuropathy. Syphilis produces a cutaneous ulcer at the site of infection — often the penis — in its primary phase; it may then go on to cause a variety of cutaneous manifestations, which could explain the rash in this patient.19 The ocular manifestations of syphilis include inflammation at all levels and layers of the eye, beginning with the cornea (syphilitic keratitis), the anterior chamber (uveitis), the vitreous and choroid (vitritis and chorioretinitis), and the optic nerve (optic neuritis). Optic neuritis may occur in two guises.20 In one form, the spirochete may involve the optic-nerve head, the peripapillary choroid, and sometimes also the brain and spinal cord. Most of the inflammatory reaction in this situation is centered on the optic-nerve head and neuro-ocular junction, and the MRI scans may not show conspicuous changes such as gadolinium enhancement.21 In the second form, optic perineuritis, a process in which the optic-nerve sheath (dura mater) is infected, may cause optic-nerve atrophy without optic-nerve edema by means of slow compression of the axons, demyelination, or vascular compromise of the vasa nervorum. In optic perineuritis, the MRI scan usually shows intense uptake of gadolinium along the optic-nerve head. In such cases, the loss of vision may occur slowly, and patients may be unaware of the deficit until it is well under way.
In summary, the most likely unifying diagnosis in this case is an infection, particularly secondary syphilis with central nervous system involvement and optic neuritis. We asked for consultation from specialists in infectious diseases.
Dr. Regina C. LaRocque: The diagnostic test result that was received was the serum rapid plasma reagin test, which was positive at a titer of 1:2048. We considered the constellation of findings — a history of a penile ulcer, a papulosquamous rash, optic neuritis, lymphocytic pleocytosis of the cerebrospinal fluid, and a positive serum rapid plasma reagin test — to be diagnostic of secondary syphilis, complicated by neurologic involvement.
Rates of syphilis have been increasing in the United States, particularly among men who have sex with men.22 This patient did not report behavior that would put him at high risk for sexually transmitted diseases, but the yield from questions about sexual history can be low. This patient's penile ulcer was almost certainly the initial chancre of primary syphilis. Secondary syphilis, a systemic illness with a wide variety of symptoms that are the clinical manifestation of disseminated infection, occurs shortly after infection and can be relapsing. Rash is the most characteristic feature of secondary syphilis. Neurosyphilis, with cerebrospinal fluid, meningeal, and ocular involvement, can occur at any time after the initial infection.
In this case, the diagnosis was confirmed by reactive serum treponemal tests (the fluorescent treponemal antibody absorption test and T. pallidum particle agglutination assay) and by a Venereal Disease Research Laboratory (VDRL) test of the cerebrospinal fluid that was positive at a titer of 1:2. We recommended treatment with intravenous penicillin in accordance with the guidelines of the Centers for Disease Control and Prevention,23 HIV testing, and partner notification and testing through the Massachusetts Department of Public Health. Follow-up cerebrospinal fluid examination and serum rapid plasma reagin testing were recommended in 3 to 6 months, after the completion of the course of penicillin. We asked our colleagues in dermatology to comment on the rash.
Dr. Daniela Kroshinsky: The patient stated that the rash had been present for approximately 1 month. There was a lightly erythematous morbilliform eruption with adherent branny, dry scale over his scalp (Figure 2A), arms, upper back, chest, and the sides of his neck, predominantly in a photodistribution. He had no lymphadenopathy or mucosal or palmoplantar lesions. The differential diagnosis of these lesions included secondary syphilis, pityriasis rosea, pityriasis lichenoides chronica, subacute cutaneous lupus erythematosus, guttate psoriasis, primary HIV infection, eczema, tinea versicolor, and a drug eruption. Because of his history, the differential diagnosis was narrowed to syphilis, pityriasis rosea, subacute cutaneous lupus erythematosus, and a drug eruption.
Pityriasis rosea is a self-limited eruption most often seen in adolescents and young adults. A large, solitary, round or oval flat lesion with a ring, or collarette, of scale, known as a herald patch, is followed by an eruption of smaller lesions most often arranged in an axial, or “fir tree,” distribution. The rash is usually asymptomatic but can be intensely pruritic. This patient was older than the usual age group for this disorder, he had not noted a herald patch, and the distribution of the rash was not characteristic.
Subacute cutaneous lupus erythematosus is characterized by photodistributed scaly patches and annular plaques. It can be drug-induced or associated with systemic lupus erythematosus (SLE), and can be associated with a false positive rapid plasma reagin test. This patient did not have a history of SLE and was not taking any medications known to cause subacute cutaneous lupus erythematosus. However, he had a lupus anticoagulant and a positive antinuclear antibody, so this diagnosis was an important consideration.
The most common drug eruption is a morbilliform rash, characterized by edematous, erythematous, flat-topped papules that can begin centrally and spread outward. The presence of scale and the distribution of this patient's rash are not typical of a morbilliform drug eruption. There have been several skin findings associated with granulocyte colony-stimulating factor (G-CSF), including injection-site reactions, papular eruptions, vasculitis, and acute febrile neutrophilic dermatosis (Sweet's syndrome).24,25 Sweet's syndrome is characterized by the sudden onset of erythematous-to-violaceous edematous papules and plaques in association with fever, as well as leukocytosis in association with an underlying malignant condition, inflammatory bowel disease, medications, or infection. Although this patient did have a hematologic malignant condition and had received G-CSF, his lesions were not characteristic and he lacked the other clinical manifestations of Sweet's syndrome.
The cutaneous findings of secondary syphilis typically occur several weeks after primary infection. Initially, the eruption can consist of faint, erythematous macules arranged over the upper torso and flanks, similar to the rash described in this case 1 month after the penile lesion was noted. Later, the lesions become more infiltrated and darker, often with scale. There is frequent involvement of the palms and soles, with dark papules surrounded by a of collarette of scale. There can be annular plaques, larger central lesions surrounded by satellite papules, or hypopigmented macules. Mucosal lesions and alopecia can also be seen. Although this patient's eruption was not characteristic, the cutaneous manifestations of syphilis can mimic almost any papulosquamous disease; in view of his history of a penile ulcer, optic neuropathy, and positive rapid plasma reagin test, we thought that the most likely diagnosis was secondary syphilis, and a skin biopsy was performed.
Dr. Misha L. Pless's Diagnosis
Secondary syphilis with optic neuritis (neurosyphilis).
Dr. Lyn M. Duncan: Examination of a skin-biopsy specimen of the central back revealed lichenoid dermatitis (Figure 2B), with focal epidermal keratinocyte necrosis and a superficial and mid-dermal perivascular infiltrate that was composed predominantly of plasma cells, with scattered lymphocytes and neutrophils (Figure 2C and 2D).
The histologic findings in secondary syphilis are variable and may be psoriasiform, pustular, or granulomatous. There is usually a superficial and deep perivascular infiltrate that occasionally displays a bandlike (lichenoid) distribution. Early lesions show a sparse perivascular lymphohistiocytic infiltrate with perivascular neutrophils, few plasma cells, and normal epidermis. Later lesions are characterized by more numerous plasma cells, endothelial swelling, and epidermal changes, including parakeratosis, hyperplasia, spongiosis, and exocytosis. Occasionally, perifollicular and periadnexal infiltrates may be observed. The findings in this case, although not specific, are consistent with syphilis.
The differential diagnosis included a cutaneous eruption in reaction to filgrastim. Cutaneous eruptions associated with medication use have several histologic patterns, most of which include a dermal infiltrate containing eosinophils. Filgrastim has also been reported to be associated with pyoderma gangrenosum, neutrophilic eccrine hidradenitis, and at the sites of injection, a lichenoid reaction.24–26 This patient's skin-biopsy specimen did not contain eosinophils, and there was minimal neutrophilic infiltration of the dermis, without substantial involvement of the eccrine units. Although there was a lichenoid pattern, the rash was not localized to injection sites.
The patient had begun treatment with penicillin at the time of the biopsy. A histochemical stain for spirochetes (Steiner stain) did not reveal organisms; immunohistochemical staining is more sensitive for detecting spirochetes in tissue sections,27 but this test also did not reveal organisms in the skin-biopsy specimen. Overall, the clinical and histologic findings most support the diagnosis of a syphilitic dermatosis.
Dr. Tucker: The patient completed a 2-week course of intravenous penicillin followed by intramuscular benzathine penicillin. He had a Jarisch–Herxheimer reaction shortly after starting therapy, characterized by fever and worsening of his rash. Results of the rapid plasma reagin test decreased from 1:2048 on admission to 1:64 at follow-up 4 months later. Repeat lumbar puncture showed no white cells and a negative cerebrospinal fluid VDRL test. Testing for antibodies to HIV was negative. The left optic-nerve head and central vision after treatment returned to near normal.
A Physician: Was the source of his infection identified?
Dr. LaRocque: No, but the case was referred to the Massachusetts Department of Public Health for contact tracing.
Dr. Nancy Lee Harris (Pathology): This case illustrates the extent to which the diagnosis of syphilis is not considered by physicians, even in the face of typical clinical manifestations. The patient had a characteristic penile lesion followed by a rash, and yet two incorrect diagnoses were made. Pathologists also can fail to consider the diagnosis of syphilis. I have seen three inguinal lymph-node–biopsy specimens in the past 2 years in which a diagnosis of Hodgkin's lymphoma was favored by the pathologist, yet the diagnosis proved to be syphilitic lymphadenitis. In none of the cases had a genital examination been performed. In this case, the penile lesion appeared 6 months after the lymph-node biopsy and the lymph nodes were cervical and mediastinal, making it unlikely that the initial diagnosis was incorrect; however, we did obtain the slides for review and confirmed the diagnosis of Hodgkin's lymphoma.
Secondary syphilis involving the skin and optic nerve (neurosyphilis).
We thank Drs. Nagagopal Venna (Neurology) and R. Gilberto Gonzalez (Neuroradiology) for advice on the conference, and Dr. Eric Bonnem (Dartmouth–Hitchcock Clinic, Manchester, NH) for his assistance in preparing the case history.
Dr. Pless reports receiving consulting fees from Bayer, EMD Serono, Pfizer, and Teva Neuroscience; gifts from EMD Serono, Pfizer, Teva, Bayer, and Novartis; grants from EMD Serono Clinical Trial; honoraria from EMD Serono, Pfizer, Teva, Bayer, and Novartis; and payment for development of educational presentations from EMD Serono, Bayer, Teva Neuroscience, and Pfizer. No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This case was discussed at the Neurology Grand Rounds, July 23, 2009.
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From the Departments of Neurology (M.L.P.), Dermatology (D.K.), Radiology (B.R.B.), and Pathology (L.M.D.), and the Division of Infectious Diseases (R.C.L.), Massachusetts General Hospital; and the Departments of Neurology (M.L.P.), Dermatology (D.K.), Medicine (R.C.L.), Radiology (B.R.B.), and Pathology (L.M.D.), Harvard Medical School — both in Boston.
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