Malignant atrophic papulosis (MAP), also known as Degos disease, is an extremely rare disease that is characterized by its unique skin presentation (namely, central, porcelain-white atrophic lesions with a telangiectatic rim). MAP has the following 2 variants: cutaneous MAP is manifested in the skin alone, whereas systemic MAP affects the gastrointestinal tract, central nervous system, lungs, and other internal organs. Some patients who presented with only cutaneous symptoms at first may develop systemic symptoms several years later. Although the exact pathologic mechanisms are unclear, Magro et al suggested in a recent study that MAP is a vascular injury syndrome that involves complement component C5b–9 complex deposition and high expression of interferon-α. The prognosis of systemic MAP is poor and typically fatal within a few years. Nonetheless, because the C5b–9 complex is detected in MAP, some researchers have suggested combined treatment with eculizumab (a humanized monoclonal antibody against C5) and treprostinil (a prostacyclin analog). Here, we report on a girl with systemic MAP who had severe central nervous system involvement and responded to eculizumab.
A 4-year-old girl was admitted to our hospital because of a sudden onset of ptosis of the left eyelid. The patient was born with middle–ring finger syndactyly in both hands and middle–fourth toe syndactyly in both feet. The patient had undergone web release and reconstruction at the age of 2 years. Two weeks before this admission, she had 1 episode of severe abdominal pain; however, blood examination and abdominal computed tomography (CT) revealed no remarkable findings. Her symptoms were relieved after supportive treatment. Her family history was unremarkable.
At the pediatric emergency department, the patient was alert and oriented, with normal psychomotor development. On examination, we observed several porcelain-white atrophic papules with rims of erythema on her trunk and thighs (Fig 1). According to her parents, the papules occurred during her infancy and gradually increased in number. Neurologic examination revealed left ptosis, lateral deviation of the left eye, and mydriasis without light reflex. No decreased muscle power or sensory loss was observed. The complete blood count, serum biochemistry, and coagulation function tests yielded normal results. An emergency brain CT scan showed effusion in the frontoparietotemporal area of the bilateral hemisphere (which was more prominent in the left side) and several calcification spots in the left cerebral cortex (Fig 2).
The patient underwent an emergency operation of the left blur hole on the left frontal scalp with external drainage on the same day. Her cerebrospinal fluid (CSF) collected during surgery revealed elevated protein concentration (776 mg/dL) only. The patient still showed left ptosis and no pupil light reflex in the left eye for the next few days. Subsequently, a skin biopsy was performed, of which the specimen revealed the focal loss of elastic fiber integrity in the upper dermis and superficial perivascular lymphocytic infiltration in the dermis. Furthermore, focal fibrinoid necrosis of the vascular wall (Fig 3A) and thrombotic microangiopathy were observed microscopically (Fig 3B). We screened for an antinuclear antibody, the complement components C3 and C4, and antiphospholipid antibodies, and the results revealed no signs of autoimmune disease.
A total of 10 days after her admission, the patient developed right facial paralysis and right arm and leg weakness. An emergency brain CT scan revealed acute infarction in her left frontal lobe and left high frontoparietal junction with marked subdural effusion and calcification in the cortex, as mentioned. Within 2 weeks, the patient’s neurologic symptoms deteriorated to aphasia, loss of swallowing ability, and total paralysis; she did not respond to pain or other stimuli. An additional episode of abdominal distention and gastric bleeding occurred 2 weeks later, with bowel distention and ileus observed on the radiograph film. For the following month, the patient was awake but completely paralyzed and could trace moving objects only with her right eye. She exhibited tachycardia of up to 130 to 150 beats per minute with sinus rhythm, intermittent abdominal fullness with indigestion, and intermittent seizure-like movements. Immunohistochemical staining of membrane attack complexes (MACs) in her skin biopsy specimen revealed MAC deposition in the vessel walls (Fig 4).
According to clinical presentation and pathologic findings, the patient was diagnosed as having malignant atrophic papulosis (MAP). The first dose of eculizumab (300 mg) was administered 2 months after her admission. The protocol was approved by the Institutional Review Board of the Taichung Veteran General Hospital, Taiwan (No. SF15161A) and the Food and Drug Administration of Taiwan (No. 1040035623). Meanwhile, we administered enoxaparin subcutaneously as an anticoagulant and depakine orally as an antiepileptic drug. Her heart rate returned to normal within 2 days. The continuous administration of eculizumab every 2 weeks markedly improved her neurologic function. After 18 months of regular eculizumab, enoxaparin, and rehabilitation, the patient had minimal facial paralysis, normal swallowing and speaking ability, and muscle power grades 4 for the left limbs and 3 for the right limbs.
The patient presented with sudden generalized seizures and bilateral pupil dilation during a 2-day trip. She was transferred to our emergency department from another hospital in a few hours, and her brain CT scan revealed multiple intracranial hemorrhages, intraventricular hemorrhage with hydrocephalus, subdural effusion in the left frontoparietal region, and multiple calcifications in the CSF space. Her parents refused additional resuscitation or operation, and she died within a few hours.
To date, ∼200 cases of MAP have been reported worldwide. The average age of disease onset is 35.4 years,1 and ∼30 cases involved children or adolescents.2,–4 Only 1 case reported eculizumab and treprostinil treatment of the central nervous system (CNS) manifestation of this disease.5
The presentation of MAP varies among patients. Studies have reported neurologic involvement in 20% to 64% of patients.1,6,–8 However, neurologic involvement was more frequent in the pediatric group in 1 study (11 of 14 patients).4 The presentations of CNS involvement included subdural effusions, hemorrhagic or ischemic strokes, disabling polyradiculoneuropathy, and other nonspecific neurologic symptoms. In our case, the first neurologic symptoms were ptosis of the left eyelid and subdural effusion, which were similar to a pediatric case reported by Karaoğlu et al.3 Elevated protein in the patient’s CSF indicated a chronic meningovascular process.3,9 Caviness et al10 reported vessel involvement in dural biopsy in a previous study.
MAP has been treated by several medical treatments, including antiplatelet agents (aspirin, dipyridamole, and clopidogrel), anticoagulants (heparin and warfarin), and immunosuppressants (corticosteroids, azathioprine, and methotrexate).11,–13 Nonetheless, no treatment has yielded satisfactory responses before the introduction of eculizumab. In 2011, Magro et al14 reported the pathologic findings of extensive deposits of C5b–9 within the cutaneous vasculature, and they proposed that inhibition of C5 might be a therapeutic approach to this disease. Eculizumab yielded favorable responses in a few cases later. Magro et al15 administered eculizumab to a 46-year-old man with MAP for more than 2 years. The clinical condition of the patient markedly improved after the initial treatment and remained stable; however, he still experienced 2 episodes of acute abdominal pain, which required surgery. The tissue biopsy specimen showed no more MAC deposits but persistently high type I interferon signature and inflammation. Oliver et al11 examined a 55-year-old woman with MAP who presented with abdominal symptoms for 5 years. After eculizumab treatment for 6 months, the patient experienced only 1 minor episode of abdominal pain. Shapiro et al5 reported marked effects of treprostinil in a patient with MAP combined with severe pulmonary hypertension. They later administered treprostinil to a 17-year-old patient who presented with recurrent abdominal pain, hematuria, and neurologic symptoms despite eculizumab treatment; the patient has subsequently been symptom-free. Thus, a long-term treatment combination of treprostinil and eculizumab is suggested.1
Before the introduction of eculizumab and treprostinil, no studies had reported an effective treatment of neurologic involvement in MAP, and surgical drainage had not been found to be effective for subdural effusion.3,10 However, the combination treatment may entail a considerable economic burden on the patient and family. Although our patient died after 18 months of eculizumab treatment, her initial response was impressive, and neurologic function showed gradual improvement. This case reveals that eculizumab can improve patients’ CNS manifestations, although its long-term effectiveness and combined use with treprostinil require additional clinical examination.
Dr Huang drafted the initial manuscript; Drs Fu and Wang conceptualized and designed the study and critically reviewed the manuscript; Dr Lee provided the pathologic photographs and wrote the description of pathological findings in the manuscript; and all authors approved the final manuscript as submitted.
FUNDING: Supported by the Taiwan Foundation for Rare Disorders (Case: TFRD104MS09-03).
The eculizumab treatment protocol was approved by the Institutional Review Board of the Taichung Veteran General Hospital, Taiwan (No. SF15161A).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.