1. GRAND ROUNDS Desiree Ong, M.D. Vanderbilt Eye Institute 12/15/06

2. Our Patient CC: “Droopy eyelid” HPI: 7 mo old male with unequal pupil size x 3 days noted by mother. Pt was evaluated at an outside ER, head CT was negative. Over the next 24 hrs, mother noticed that left eyelid began to droop.

3. History POHx: none PMHx: full-term, normal birthweight, no complications FHx: no eye disease, healthy 6 yo sibling Social hx: non-contributory Allergies: NKDA Meds: none

4. Exam VA: Fixes and follows Pupils: OD bright 4-->3mm dim 5.5-->4.5mm OS bright 2.5-->2mm dim 2-->1.5mm Motility: grossly full OU Tp: soft to palpation OU

6. Exam continued PLE –External: palpebral fissure OD 9mm, OS 6mm, small movable cervical nodes left>right –Lids/lashes: quiet OU, mild ptosis OS –S/C: quiet OU –K: quiet OU –A/C: formed OU –Iris: intact OU –Lens: clear OU DFE –WNL OU, C/D 0.2 OU

7. Sympathetic Pathway

8. Differential diagnosis? Acquired Pediatric Horner Syndrome

9. Differential Diagnosis Acquired Pediatric Horner Syndrome First-order lesions (hypothalamus to C8-T2) –Meningitis –Basal skull tumors, pituitary tumor –Brain stem vascular malformation –Cerebral vascular accident –Demyelinating disease –Intrapontine hemorrhage –Neck trauma/cervical disk disease Second-order (preganglionic) lesions (T1 to SCG) –Neuroblastoma –Lymphadenopathy (reactive or malignant) –Apical lung tumors –Metastases –Mandibular tooth abscess –Lesions of the middle ear (eg, acute otitis media) –Thyroid adenoma –Thoracic aorta, subclavian or common carotid artery aneurysm –Trauma/surgical injury/chest tube/central venous catheter

10. Third-order lesions (SCG to post-ganglionic neurons) –Internal carotid dissection/aneurysm/vasopasm –Extension of cavernous sinus tumor, nasopharyngeal tumor –Carotid cavernous fistula –Cluster/migraine headaches –Herpes zoster –Otitis media –Neck trauma/tumor (i.e. rhabdomyosarcoma)/inflammation Drugs –Bupivacaine –Chlorprocaine –Chlorpromazine –Deserpidine –Diacetylmorphine –Diethazine –Fluphenazine –Guanethidine –Influenza virus vaccine –Levodopa - Lidocaine - Mepivacaine - Mesoridazine - Oral contraceptives - Procaine - Prochlorperazine - Promethazine - Propoxycaine - Reserpine - Thioridazine

11. Lab Results Pt was admitted for observation CXR: negative MRI/CT brain/chest/abdomen: negative CBC, CMP, HVA/VMA urine tests were WNL LDH was elevated at 552

17. Horner Syndrome Ptosis - denervation of Müller muscle “Reverse ptosis” - lower lid elevation Miosis - greater in dim light (dilation lag) Anhidrosis – impaired flushing and sweating –First-order: ipsilateral body –Second-order: ipsilateral face –Post-ganglionic (third-order): absent or limited Iris heterochromia – affected iris is lighter - Congenital or children < 2 yrs - Long-standing lesions

18. Other associations First-order lesions: –Hemisensory loss, weakness, dysarthria, dysphagia, ataxia, vertigo, and nystagmus Second-order lesions: –H/o trauma/surgery, facial/neck, axillary/shoulder or arm pain/swelling, cough, hemoptysis Third-order lesions: –Diplopia (CN VI palsy), numbness/pain in V1 and V2 Cluster headaches –may cause temporary or permanent Horner syndrome

19. Testing No standard evaluation protocol Previous studies suggested that a h/o birth trauma or urine studies alone is sufficient 3 CBC, FTA-ABS, VDRL, PPD VMA and HVA urine tests –positive in 90-95% with neuroblastomas –localized tumors may be associated with normal urine studies 2 MRI/MRA, extracranial Doppler, and/or chest x-ray

20. Testing Cocaine (4% or 10%) –Inhibits the re-uptake of norepinephrine –Denervation  poor dilation regardless of level –Anisocoria greater than 0.8 mm = positive Apraclonidine (0.5% or 1%) –Alpha-receptor agonist –Denervation supersensitivity of the iris dilator –Reversal of anisocoria = positive

21. Chen et al. (2006) Small randomized crossover study (10 pts) Testing with 0.5% apraclonidine and 4% cocaine Mean differences in pupil diameter -before/after 4% cocaine = -2.08/-2.97 mm (p=0.0047) -before/after 0.5% apraclonidine = -2.04/+1.08 mm (p=0.005) Conjunctival hyperemia in two patients Conclusion: 0.5% apraclonidine is safe and effective for diagnosis of Horner syndrome in children Chen PL, Chen JT, Lu DW, Chen YC, Hsiao CH. Comparing efficacies of 0.5% apraclonidine with 4% cocaine in the diagnosis of Horner syndrome in pediatric patients. J Ocul Pharmacol Ther. 2006 Jun;22(3):182-7.

22. Testing Hydroxyamphetamine 1% (Paredrine) –Stimulates presynaptic norepinephrine release –Distinguishes presynaptic from postganglionic lesions –40-97% sensitive; inaccurate within 24-48 hours of cocaine test –Failure of affected pupil to dilate equally or greater to normal pupil = third-order lesion

23. Mahoney et al. (2006) Retrospective review (56 children) 28 (50%) had no previously identified cause - 18 with complete imaging and urine studies - Mass lesions found in 6/18 (33%); 4 had neuroblastoma; all negative urine studies Of all patients, 13/56 had a neoplasm (23%) Conclusions: - Urine testing alone is inadequate - Recommend physical exam with palpation - MRI brain/neck/chest, VMA and HVA by spot Mahoney NR, Liu GT, Menacker SJ, Wilson MC, Hogarty MD, Maris JM. Pediatric Horner syndrome: etiologies and roles of imaging and urine studies to detect neuroblastoma and other responsible mass lesions. Am J Ophthalmol. 2006 Oct;142(4):651-9

24. Cervical Lymphadenopathy in Children Acute bilateral - adenovirus, influenza, RSV; EBV and CMV Acute unilateral - strep or staph (40-80%) Indications for biopsy: - Persistent enlargement - Solid fixed or supraclavicular mass - Constitutional signs and symptoms Increased risk for malignancy: 8 - Generalized LAD - LAD > 3 cm - Hepatosplenomegaly - High LDH levels

25. Cervical Lymphadenopathy in Children Subacute/chronic LAD –Cat scratch, mycobacteria, and toxoplasmosis –EBV, CMV, histoplasmosis, HIV –Leukemia, lymphoma, neuroblastoma, rhabdomyosarcoma, and nasopharyngeal carcinoma Laboratory tests are not necessary in majority Most cases are self-limited and require no treatment

26. Cervical Lymphadenopathy

27. Oguz et al. (2006) - Retrospective review -457 children aged 2 mo -19 yrs -76% benign, 24% malignant -61% of the benign group had an unknown etiology -Most common benign etiologies: EBV and acute lymphadenitis -Most common malignant: Hodgkin’s and NHL -None in the infant group had a malignant process Oguz A and Karadeniz C. Evaluation of Peripheral Lymphadenopathy in Children. Pediatric Hematology and Oncology. 23:549-561, 2006.

28. Our Patient Started on Unasyn Improvement was noted over the next few days Repeat CT showed decreased necrosis Persistent Horner syndrome, monitored closely Recently started on 10 days of Omnicef for a persistent otitis media/URI

29. Take Home Points Horner syndrome may be the first symptom of a potentially serious condition Children with Horner syndrome should undergo a thorough physical exam with urine testing and MRI Acute cervical lymphadenopathy in children usually has an infectious cause but should be monitored closely

30. References 1.Chen PL, Chen JT, Lu DW, Chen YC, Hsiao CH. Comparing efficacies of 0.5% apraclonidine with 4% cocaine in the diagnosis of Horner syndrome in pediatric patients. J Ocul Pharmacol Ther. 2006 Jun;22(3):182-7. 2.Fritsch P, Kerbl R, Lackner H, et al. “Wait and see” strategy in localized neuroblastoma in infants: an option not only for cases detected by mass screening. Pediatr Blood Cancer 2004;43:679-682. 3.George ND, Gonzalez G, Hoyt CS. Does Horner's syndrome in infancy require investigation? J Ophthalmol. 1998 Jan;82(1):51-4 4.Leung AK, Robson WL. Childhood cervical lymphadenopathy. J Pediatr Health Care. 2004 Jan-Feb;18(1):3-7 5.Mahoney NR, Liu GT, Menacker SJ, Wilson MC, Hogarty MD, Maris JM. Pediatric horner syndrome: etiologies and roles of imaging and urine studies to detect neuroblastoma and other responsible mass lesions. Am J Ophthalmol. 2006 Oct;142(4):651-9 6.Oguz A and Karadeniz C. Evaluation of Peripheral Lymphadenopathy in Children. Pediatric Hematology and Oncology. 23:549-561, 2006. 7.Sauer C, Levingohn MW. Horner's syndrome in childhood. Neurology. 1976 Mar;26(3):216-20 8.Twist CJ. Assessment of lymphadenopathy in children. Pediatr Clin North Am 2002;49(5):1009-1025. 9.Yaris N et al. Analysis of Children with Peripheral lymphadenopathy. Clinical Pediatrics. 2006;45:544-549.