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A 7 Year Old with Chronic Droopy Eyes, Weakness in Head/Neck Control, and an Abnormal Gait Agarwal Sonika, Timothy E. Lotze, Suzanne L. Woodbury

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S1071-9091(14)00032-1 10.1016/j.spen.2014.04.013 YSPEN479

To appear in: Semin Pediatr Neurol

Cite this article as: Agarwal Sonika, Timothy E. Lotze, Suzanne L. Woodbury, A 7 Year Old with Chronic Droopy Eyes, Weakness in Head/Neck Control, and an Abnormal Gait, Semin Pediatr Neurol , 10.1016/j.spen.2014.04.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

A 7 year old with chronic droopy eyes, weakness in head/neck control, and an abnormal gait.

Agarwal Sonikaa Lotze Timothy Eb Woodbury Suzanne Lc

a,b

Department of Child Neurology, Baylor College of Medicine, Houston, Texas, USA

c

Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, Texas, USA

From: Departments of Child Neurology and Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, Texas 77030

Keywords: myasthenia gravis, Lambert-Eaton myasthenic syndrome, children, EMG, diabetes, autoimmune, neuromuscular

Financial Disclosure Statement: Dr. Agarwal reports no disclosures Dr. Lotze reports no disclosures Dr. Woodbury reports no disclosures

Word Count: Abstract: 80 Text: 1581

Dr. Agarwal – study concept, data acquisition and manuscript writing Dr. Lotze - study concept, data acquisition and critical revision of the manuscript Dr. Woodbury - study concept, data acquisition and critical revision of the manuscript

ABSTRACT Lambert-Eaton myasthenic syndrome (LEMS) is a rare disorder of presynaptic neuromuscular transmission. Clinical features include muscle weakness and fatigability, a- or hyporeflexia and autonomic dysfunction. High frequency repetitive nerve stimulation shows incremental response and almost 90 % patients have antibodies against the voltage-gated calcium channels. LEMS is often associated with small cell lung cancer or other neoplasms or with autoimmune diseases. We report a case of nonneoplastic LEMS in a three year old child with associated comorbid autoimmune diabetes.

CASE REPORT Our patient is a 7 year old female, who presented at age 3 with features of droopy eyes, weakness in head/neck control, inability to hop and jump and an abnormal gait. She was initially evaluated at an OSH and started on pyridostigmine with suspicion of myasthenia gravis and then referred to our center for further evaluation. At the time of her hospitalization, she was reported to have improvement in her ptosis and stamina with pyridostigmine, without much benefit in her gross motor activities, inability to run and jump, and difficulty in getting up from lying and sitting position. History was negative for pain, fever, swallowing or breathing difficulty. She was born full term with an uneventful pregnancy, labor and childbirth and had a previously normal development. There was no history suggestive of hypotonia or weakness in the neonatal period or

thereafter. Past medical history was negative and there was no evidence of neurologic, genetic or rheumatologic disorders in the family. On examination, she was of average weight and built, with an unremarkable general, cardiac, pulmonary, abdominal examination. Neurologic evaluation showed ptosis in neutral gaze, which disappeared with sustained upward gaze, no ophthalmoplegia, symmetric smile and normal tongue movement without fasciculation. Axial and appendicular tone was low without any wasting or polymnimyoclonus. Motor strength was notable for proximal muscle weakness more in lower extremity compared to upper, with power in range of 4 to 5 for most muscle groups. There was areflexia, intact sensation, and gait was trendelenberg with intact toe walking. A through laboratory work up revealed a normal complete blood count, differential and platelet count, liver function tests, antinuclear antibody, antiphospholipid antibody, serum creatinine kinase, aldolase and thyroid function tests. She had a mild elevation of LDH (211, upper limit of normal 192) and previous test showing acetylcholine receptor antibody with mild elevation to 23 (upper limit 20). Her glucose was elevated, with elevation of insulin antibody (19.3), ICA-512 autoantibody and GAD antibody. She was diagnosed with autoimmune comorbid diabetes type I and started on insulin after an endocrine consult. A search for neoplasm with a CT scan of chest, abdomen and pelvis was negative. A MRI brain was done for evaluation of questionable early puberty manifesting as vaginal discharge and advanced bone age, and was negative for tumor. Pelvic ultrasound revealed a slightly prominent uterine stripe, and xray of hand and wrist revealed bone age within 2 S.D of mean. Ophthalmological evaluation during the course of work up revealed cataracts consequent to poorly

controlled diabetes and her subsequent scans have shown her to be cancer free. The test for LEMS voltage gated calcium channel antibody was positive. Electromyography and Nerve stimulation study was done (Figure 1) confirming the diagnosis with incremental response post exercise. The patient was initially continued on the pyridostigmine with dose adjustment to 6 mg/kg/d divided 4 times a day, for clinical improvement, along with physical therapy and aquatherapy. On subsequent follow up visit considering the poor gain in motor skills, she was started on pulse intravenous immunoglobulin (IVIG) infusions which have been continued at intervals of 4-6 weeks. Also, 4-aminopyridine was added, with improvement in muscle power. Her most notable deficits seem to be in her core muscle strength with persistent head lag. She continues to have episodes throughout the day in which she has some ptosis and decreased stamina. Vitamin D3 1000 units was started with potential for benefit in autoimmune diseases. On her follow up in April 2012, she was noted to have continued limitation of activities due to LEMS, with fatigue and significant weakness. Neurologic exam was notable for bilateral ptosis, motor strength 3-4/5 in neck and upper extremities and 4-5/5 in lower extremities, with 1+ reflexes bilaterally. Cellcept was added to the treatment regimen and the IVIG was scaled back to every 6 weeks, due to doubtful benefit. We discussed options of plasmapheresis and rituximab as the next steps if the current regimen does not show further improvement.

DISCUSSION Lambert-Eaton myasthenic syndrome (LEMS) is a rare disorder of presynaptic neuromuscular transmission, characterized by muscle weakness and fatigability, a- or hyporeflexia and autonomic dysfunction, without significant ocular or bulbar involvement. The juvenile population represents only 5 % of the reported cases.1 High frequency repetitive nerve stimulation shows incremental response and almost 90 % patients have antibodies against the voltage-gated calcium channels. 2,3 The possible association of LEMS with neoplasm requires active search for possible malignancy, however 30 % of the patients do not develop cancer.1,4 LEMS is often associated with small-cell cancer or other neoplasms in adults, and about a third of patients have association with autoimmune diseases.5,6,. LEMS was first described by Lambert et al in 1956 as a myasthenic syndrome with proximal muscle weakness, easy fatigability and association with neoplasms. 5 Since then, LEMS has been diagnosed in association with a variety of neoplasms.6,7 An autoimmune association has also been seen in numerous cases, as seen in our case.6 Our patient had clinical evidence of comorbid immune-mediated diabetes, as evidenced by presence of autoimmune response against the pancreatic beta cells, elevation of insulin antibody (19.3), ICA-512 autoantibody and GAD antibody. Hoffman et al had reported a case of LEMS in a 10-year old child with Graves disease, alopecia totalis, vitiligo, psoriasis, urticaria, IgA deficiency and association with HLA DR3 and DR17, and the presence of autoimmune thyroid disease, islet cell and parietal cell antibodies.8

However since the association with cancer versus autoimmune diseases is not distinctly defined, careful follow up for malignancy is important, as is evaluation for the development of other autoimmune associated disorders.7 Approximately 90 % of the patients have antibodies against the voltage-gated calcium channels (VGCCAb), though only three of the previously published pediatric LEMS had tested positive.2,9 Our patient is the fourth to have association with VGCCAb. These antibodies interfere with the release of acetylcholine at the presynaptic part of the neuromuscular junction, thus causing clinical symptoms of weakness and fatigability. Our patient experienced progressive muscle weakness, poor axial and truncal control, ptosis and easy fatigability. She had initial improvement in motor function and response with pyridostigmine and addition of pulse IVIG therapy, with less marked benefit in the second year after diagnosis, thus necessitating addition of 4aminopyridine. Therapies with 4-aminopyridine, IVIG, pyridostigmine, prednisone have been tried in both adult and pediatric cases 9,10,11 Pediatric patients have shown benefit from IVIG or plasmapheresis briefly, and in some studies have shown sustained responses to cyclosporine with regain of normal activity over 2 to 3 years.2 Immunosuppresive agents such as azathioprine have been tried in adult patients.11 We have started our patient on mycophenolate as there was continued weakness and poor motor strength on treatment with combination of pyridostigmine, 4-aminopyridine and IVIG. Rituximab and plasmapheresis are the next steps under consideration in the coming months of follow up if benefit with current therapies is not evident. It has also been a challenge to manage the comorbid diabetes and its sequelae in these patients.

Brady et al have reported a new type of possible congenital LEMS in a 4 year old girl who had been hypotonic and areflexic since birth with delayed motor development. Although the initial testing was consistent with congenital myopathy, the EMG at 30 days and 1 year did not include repetitive stimulation studies.12 The incremental response at rapid stimulation in the EMG at 3 year follow up was suggestive of LEMS, as was the positive result seen after guanidine trial.12 To the best of our knowledge, our case is the youngest patient with nonneoplastic LEMS, associated with comorbid diabetes and positive VGCCAb. We emphasize the importance of testing for VGCCAb, and a thorough search for autoimmune disorders in addition to work up for cancer in pediatric patients of LEMS.

REFERENCES 1. Wirtz PW, Smallegange TM, Wintzen AR, Verschuuren JJ. Differences in clinical features between the Lambert-Eaton myasthenic syndrome with and without cancer: an analysis of 227 published cases. Clin Neurol Neurosurg 2002 Sept;104:359-63 2. Tsao CY, Mendell JR, Friemer ML, Kissel JT. Lambert-Eaton myasthenic syndrome in children. J Child Neurol 2002;187:74-76. 3. Mototmura M, Lang B, Johnston I, et al. Incidence of serum anti-P/Q-type and antiN-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Journal of Neurological Sciences 1997;147:35-42. 4. Lambert EH, Rooke ED. Myasthenic state and lung cancer In: Brain W, Norris FH, eds. The Remote Effects of Cancer on the Nervous system. Vol I. New York:Grune and Stratton, 1965:67-80. 5. Lambert EH, Eaton LM, Rooke ED.Defect of neuromuscular conduction associated with malignant neoplasms. Am J Physiol 1956;187:612-613. 6. Engel AG. Myasthenic syndromes, in Engel AG, Franzini-Armstrong C (eds):Myology New York, McGraw-Hill 1994; 1800-1806. 7. O’Neill JH, Murray NMF, Newsom-Davis J:The Lambert Eaton myasthenic syndrome. A review of 50 cases. Brain 1988;111:577-596.

8. Hoffman WH, Helman SW, Sekul E, Carroll JE, Vega RA. Lambert-Eaton myasthenic syndrome in a child with an autoimmune phenotype. Am J of Medical genetics 2003; 119A:77-80. 9. Kostera-Pruszczyk A, Ryniewicz B, Rowinska-Marcinska K, Dutkiewicz M, Kaminska A. Lambert-Eaton myasthemnic syndrome in childhood. European J of Pediatric Neurology 2009; 13: 194-196. 10. Bain PG, Motomura M, Newsome-Davis J, et al: Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology 1996; 47:678-683. 11. Kokontis L, Gutmann L. Current treatment of neuromuscular diseases. Arch Neurol 2000; 57:939-943. 12. Brady B, Chauplannaz G, Carrier H. Congenital Lambert-Eaton myasthenic syndrome. Journal of Neurology, Neurosurgery and Psychiatry. 1987; 50:476-478.

3 Hz repetitive stimulation,  ulnar nerve 

Amp  mV 

Decrement

Facilitation





At rest 

1.0 

‐19.4

100

Immed. after exercise 

2.3 

‐15.3

243

4 minutes after exercise 

1.0 

‐21.8

99.5

  Baseline 3 Hz repetitive stimulation   with decrement of 19.4%   Rep Nerve Stim R ABD DIG MIN (UL)

  500 mcV/div, 30 msec/div      Immediately post‐exercise with facilitation of 243%  

Rep Nerve Stim R ABD DIG MIN (UL)

  500 mcV/div, 30 msec/div   Figure 1 

A 7-year-old child with chronic droopy eyes, weakness in head-neck control, and an abnormal gait.

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