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CASE REPORT
Year : 2020  |  Volume : 15  |  Issue : 3  |  Page : 290-293
 

Freiberg’s infarction as the first clinical presentation of Sneddon syndrome


Neurology Section, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

Date of Submission26-Nov-2019
Date of Decision29-Jan-2020
Date of Acceptance27-Mar-2020
Date of Web Publication06-Nov-2020

Correspondence Address:
Dr. Debopam Samanta
1 Children’s Way, Little Rock, Arkansas.
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpn.JPN_159_19

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   Abstract 

Sneddon syndrome is a rare, non-inflammatory vasculopathy that generally occurs in the third to fourth decade of life but may rarely present in the pediatric population. It is characterized by the skin finding of livedo racemosa and recurrent ischemic strokes. Other common neurologic manifestations include migraine and early cognitive decline. It may be associated with systemic lupus erythematosus (SLE) and antiphospholipid antibodies, or as in our case, thrombophilia and autoimmune workup may be negative. Optimal treatment for Sneddon syndrome is unknown. Here we report the case of an 18-year-old female, with a 3-year history of livedo racemosa and migraines, who presented with acute expressive aphasia and was found to have an ischemic stroke and an evidence of prior strokes on magnetic resonance imaging (MRI). Autoimmune and cardioembolic causes of stroke were ruled out. Given the findings of livedo racemosa and evidence of recurrent strokes, she was diagnosed with Sneddon Syndrome. Five years earlier, she had been diagnosed with Freiberg disease, which is the avascular necrosis of the second metatarsal head and was likely her first symptom of Sneddon syndrome. This is the first report of Freiberg disease associated with Sneddon syndrome. This paper highlights a rare cause of stroke in the pediatric population as well as the first report of avascular necrosis associated with Sneddon syndrome. Several manifestations of Sneddon syndrome can precede strokes by years. An awareness of those features may allow for the adoption of primary stroke prevention.


Keywords: Antiphospholipid antibodies, Freiberg disease, ischemic strokes, livedo racemosa, Sneddon syndrome


How to cite this article:
Samanta D, Cobb S. Freiberg’s infarction as the first clinical presentation of Sneddon syndrome. J Pediatr Neurosci 2020;15:290-3

How to cite this URL:
Samanta D, Cobb S. Freiberg’s infarction as the first clinical presentation of Sneddon syndrome. J Pediatr Neurosci [serial online] 2020 [cited 2020 Nov 24];15:290-3. Available from: https://www.pediatricneurosciences.com/text.asp?2020/15/3/290/300045




Ischemic stroke is more common in the older population, but it also occurs in the pediatric age-group, resulting in significant morbidity and mortality. The most common etiologies for ischemic stroke in children include cardiac abnormalities, vascular lesions, hematologic abnormalities, infection, head and neck trauma, and genetic conditions. We report an 18-year-old with acute ischemic stroke secondary to  Sneddon syndrome More Details, which is rarely considered and encountered in this age-group.


   Case Description Top


A 13-year-old previously healthy girl presented in the orthopedic clinic for a 1.5-year history of right foot pain without any preceding injury. The pain persisted in spite of taking rest, wearing a boot, use of insole, and corticosteroid injection. An X-ray was done, and it revealed a Freiberg infraction of the second right metatarsal, which is a type of avascular necrosis. At the age of 15, she developed a gradually progressive erythematous rash on the trunk and proximal upper and lower extremities. She also developed intermittent headaches consistent with migraine at the same time. During a routine sports physical examination, she was noted to have a grade I/VI systolic murmur. Ultimately, she was diagnosed with a patent foramen ovale by a bubble study. Otherwise, her echocardiogram at that time revealed a structurally normal heart, and her electrocardiogram (ECG) was normal except a shortened PR interval (106ms) without any evidence of preexcitation syndrome.

At the age of 18 years, she presented to the emergency department due to acute-onset speech difficulty and headache while she was driving her car. In the emergency department, she was given a presumptive diagnosis of complicated migraine and received clonidine, lorazepam, midazolam, and prochlorperazine. She was hypertensive but thought to be secondary to pain response. She was sedated after receiving these medications and was discharged home after normalization of her blood pressure. On awakening from sleep, she was noted to have persistent speech difficulty. As the speech disturbance was persistent for more than 24h, her parents decided to bring her to our emergency department. On arrival to our hospital, her blood pressure was again elevated at 190/112mm Hg, and she had a marked tachycardia. She was given nifedipine, and a stroke code was activated due to her speech difficulty. The National Institutes of Health (NIH) Stroke Scale score was three at 28h from the onset of symptoms. She had significant expressive aphasia with incoherent and effortful speech when describing a picture. She also had significant difficulty with object naming and word repetition. She was able to follow commands and seemed to have fully intact comprehension. The rest of the neurologic examination, including cranial nerve, motor, the sensory, and cerebellar function, was normal. A stroke protocol brain magnetic resonance imaging (MRI) showed an acute left middle cerebral artery (MCA) infarct. There was also right parietal and right cerebellar encephalomalacia consistent with prior infarcts [Figure 1]. MR angiography of the head and neck was normal. There were no other stroke risk factors except for the use of estrogen-containing birth control pills for the last 3 years to regulate her menstrual cycle. There was no family history of stroke or autoimmune disease.
Figure 1: Fluid attenuated inversion recovery image (left) shows gliosis and encephalomalacia in the right parietal lobe and signal changes over the left posterior frontal cortex. There is also evidence of encephalomalacia in the inferior cerebellum, particularly on the right side (not included in the image). Diffusion-weighted imaging (DWI- right image) shows acute ischemic infarction on the left posterior frontal cortex. Please note the mild prominence of the sulci and ventricles compatible with global mild atrophy

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Given the presence of the patent foramen ovale, it was initially thought that cardiac emboli were the probable etiology of her recurrent infarcts, and she later underwent transcatheter closure of the foramen ovale. However, her general physical examination revealed a hyperpigmented rash in a thick branching and broken netlike pattern on the trunk and proximal upper and lower extremities [Figure 2]. This discoloration did not improve with warming and was consistent with a diagnosis of livedo racemosa. Owing to the findings of recurrent strokes, hypertension, and livedo racemosa, she was clinically diagnosed with Sneddon syndrome. She was started on daily aspirin and was advised to stop her hormonal contraceptive. A renal ultrasound with Doppler was normal. Her persistent hypertension was ultimately controlled with a combination of labetalol and amlodipine. She had extensive and unremarkable workup for hypercoagulability, including normal factor 5 assay, protein C activity, protein C antigen, protein S activity, protein S antigen, lipoprotein A, homocysteine, antiphospholipid syndrome (APS) panel, anticardiolipin immunoglobulin (Ig) G/IgM, antithrombin III, lipid panel, prothrombin G20210A gene mutation, factor V Leiden R506Q mutation, beta 2 glycoprotein IgG of IgM antibody, antinuclear antibodies (ANA), and antineutrophilic cytoplasmic antibodies (ANCA). Computed tomography (CT) angiogram of chest, abdomen, and pelvis did not reveal any possible vascular occlusion or narrowing of vessels. Systemic lupus erythematosus (SLE), polyarteritis nodosa, cryoglobulinemia, livedoid vasculitis, and cold agglutinin disease were excluded in this patient with appropriate laboratory tests. Cardioembolism was in the differential, though ultimately thought unlikely to be primarily responsible considering the clinical features of prominent skin manifestation and the presence of hypertension. Isolated central nervous system (CNS) angiitis and systemic vasculitis were excluded due to the absence of other systemic symptoms, normal sedimentation rate, and the absence of inflammation in the CNS. At 6-week follow-up, she was noted to have only mild expressive aphasia and did not have any recurrent stroke.
Figure 2: Dusky erythematous–violaceous, an irregular netlike pattern of livedo racemosa is seen over the trunk and extremities

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   Discussion Top


Sneddon syndrome is a noninflammatory thrombotic vasculopathy and generally occurs in the third or fourth decade of the life, although it has been reported in as young as 10 years of age.[1] Here we report a patient with Sneddon syndrome who first presented after Freiberg’s infarction—osteonecrosis of the second metatarsal head [Figure 3]. Clinical hallmarks of Sneddon syndrome are widespread livedo racemosa and ischemic strokes. Owing to the absence of a definite biomarker, this rare disease is particularly difficult to diagnose. Our patient had evidence of livedo racemosa and frequent migraines from the age of 15 years; both are common symptoms of Sneddon syndrome. However, the first symptom in our patient related to Sneddon syndrome is probably avascular necrosis of the second metatarsal head. Avascular necrosis occurs due to interruption of the blood supply of the bone; this is particularly seen in bones with a single terminal blood supply. The pathogenesis is multifactorial, including disorders of the coagulation system. Underlying thrombophilia, especially SLE associated with antiphospholipid antibodies, is a known risk factor for avascular necrosis. This is the first pediatric report of Freiberg’s infarction in a patient with Sneddon syndrome.
Figure 3: Flattening of the second metatarsal head (arrow) is seen consistent with Freiberg infraction. Please note a large osseous formation (dashed arrow) between the second metatarsal–phalangeal joint, located dorsal to the head of the second metatarsal

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Three forms of the Sneddon syndrome have been described: (1) in association with SLE, (2) APS related, and (3) a primary type with negative autoimmune and antiphospholipid antibodies. The pathogenesis of the basic thrombotic process in the primary Sneddon syndrome is currently unknown. Various other thrombophilia abnormalities were reported inconsistently in this subgroup. In our patient, extensive thrombophilia and autoimmune panel testing did not reveal any abnormality. Many experts postulate that a nonvasculitic, progressive pathology involving small- and medium-sized arteries may be primarily responsible for causing proliferation of the intima and media layers. Fibrotic occlusion and recanalization evident in the scarcely available neuropathology samples. However, it is currently unknown if a genetic mutation or a primary endothelial dysfunction from an autoimmune etiology triggers this vasculopathic process.

Hemiparesis, sensory disturbances, aphasia, and visual field defects are the most common manifestations from the ischemic strokes. Different topographic patterns of stroke types are seen, including small distal, large corticosubcortical, and small deep infarcts. Ischemic infarcts involving the territory of the superficial MCA have been reported most commonly. MR angiograms are usually normal as noted in our patient. The diffusion-weighted sequence does not usually show a pattern consistent with embolic infarcts, and may indirectly indicate a pathogenic process involving an in situ mechanism associated with cerebral vasculopathy. Cerebral angiography may show abnormality with stenosis and/or occlusion of middle- or small-sized intracranial arteries and sometimes leptomeningeal and transdural collateral networks.

Dusky erythematous–violaceous, irregular netlike pattern of livedo racemosa is a physical finding, which can be seen in numerous underlying etiologies, including normal response to cold environment (resolve with rewarming), vessel wall pathology (vasculitis, calciphylaxis, and Sneddon syndrome), underlying autoimmune connective tissue disease, intraluminal pathology due to hypercoagulability, medications (amantadine, quinidine, and catecholamine), and infections. Other etiologies were excluded in our patient by an extensive laboratory testing. This skin lesion usually precedes the onset of stroke for many years; however, it may only be given any significance after the diagnosis of stroke. The characteristic appearance is caused by a persistent impairment of peripheral blood flow due to the occlusion of small- and medium-sized arteries, in contrast to the temporary vasoconstriction seen in typical livedo reticularis, which usually improves with warming. Raynaud’s phenomenon and widespread cutaneous discoloration due to systemic angiomatosis have also been described.

High prevalence of heart valve abnormalities has also been reported in primary Sneddon syndrome; however, its role in ischemic strokes has been debated. Approximately half of the patients in a large cohort of 53 (80% women with a median age of 40 years), had valvular heart disease. However, it did not influence the type of infarcts in these patients, which suggest that the strokes were likely due to cerebral vasculopathy involving medium- and small-sized superficial and deep perforating arteries rather than due to multiple embolizations from the heart.[2] Our patient did not have any valve abnormalities but did have a patent foramen ovale with right to left shunt.

Other neurologic manifestations include diffuse cortical atrophy, early-onset dementia, psychiatric disturbances, migraines, epilepsy, intracranial hemorrhage, and movement disorders. Etiology of diffuse cortical atrophy is currently unknown. Recurrent small cortical infarcts, chronic diffuse ischemia due to diffuse stenosis of distal arteries, and white matter abnormalities with axonal loss have been postulated as probable etiologies. The MRI obtained in our patient showed mild atrophy, and she will need a close neuropsychological follow-up to detect subtle cognitive deterioration and any appearance of psychiatric disturbances.

Approximately 50% of these patients have migrainous headaches as seen in our patient.[3] Presence of migrainous headaches and widespread livedo reticularis may alert physicians about the possibility of Sneddon syndrome as both of these can precede stroke by many years. This raises the possibility of primary prophylaxis with an antiplatelet or anticoagulant agent. However, a systematic study in a large cohort is needed to know the benefit of primary stroke prevention in this group of patients.

Optimal management to prevent strokes is unknown in patients with primary Sneddon syndrome. In aPL-positive patients, anticoagulant was found to be more effective than antiplatelet agents to prevent recurrent strokes. However, no significant difference was found in the risk of recurrence between antiplatelet and anticoagulation therapies in primary Sneddon syndrome, and due to a lower risk of hemorrhage, antiplatelet therapy has been used as a first-line therapy. Hypertension occurs in a significant proportion of patients. Oral contraceptives and hypertension are correlated with disease progression. Our patient was aggressively treated for hypertension, and hormonal contraceptive was stopped.

This paper highlights a rare cause of stroke in the pediatric population as the list of potential stroke etiologies among this population is extensive and sometimes challenging for a prompt and accurate diagnosis. To the best of our knowledge, this is the first pediatric report of Freiberg’s infarction in a patient with Sneddon syndrome. As several manifestations can precede strokes by several years in Sneddon syndrome, an awareness of those features and the adoption of a primary prevention approach such as aggressive control of hypertension and avoiding hormonal contraceptives can be helpful.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Wu S, Xu Z, Liang H Sneddon’s syndrome: a comprehensive review of the literature. Orphanet J Rare Dis 2014;9:215.  Back to cited text no. 1
    
2.
Bottin L, Francès C, de Zuttere D, Boëlle PY, Muresan IP, Alamowitch S Strokes in Sneddon syndrome without antiphospholipid antibodies. Ann Neurol 2015;77: 817-29.  Back to cited text no. 2
    
3.
Zelger B, Sepp N, Stockhammer G, Dosch E, Hilty E, Ofner D, et al. Sneddon’s syndrome. A long-term follow-up of 21 patients. Arch Dermatol 1993;129:437-47.  Back to cited text no. 3
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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