Journal of Neuro-Ophthalmology, March 2009, Volume 29, Issue 1

Letters to the Editor

LETTERS TO THE EDITOR Opsoclonus Caused by Diphenhydramine Self-Poisoning We report a patient who developed opsoclonus together with coma, seizure, autonomic disturbance, and rhabdomyolysis from diphenhydramine overdose. This is the second case report of opsoclonus in this setting (1). A 22-year-old man was found unconscious in bed. Shortly thereafter, he developed a generalized seizure. In our hospital, his body temperature was 36.6°C, blood pressure was 142/90 mmHg, and pulse rate was 153 beats/min. He was unresponsive to painful stimuli. His pupils were dilated and sluggishly reactive to direct light. He had rapid conjugate oscillations of the eyes in the horizontal, vertical, and rotatory planes interpreted as opsoclonus. Abnormal blood test results included hematocrit of 53.1%, white blood cell count of 22,900/mm3, pH of 6.837, anion gap of 33 mEq/L, serum creatinine of 1.32 mg/dL, and creatine kinase of 292 IU/L. Results for plasma glucose, electrolytes, and ammonia were within normal ranges. The Triage Drugs of Abuse Panel (BIOSITE, Inc., San Diego, CA) detected no benzodiazepines or tricyclic antidepressants or their metabolites in the urine. Electro-encephalography showed diffuse beta waves without epileptiform activity. Results of brain MRI and lumbar puncture were normal. Several hours after the patient's admission, his serum creatine kinase level rose to 72,312 IU/L, and oliguric acute renal failure occurred. At this time, a family member found empty diphenhydramine packages in the patient's room, suggesting self-poisoning with this agent. We treated the patient with intravenous fluids, furosemide, and 800 mg valproic acid daily. Opsoclonus disappeared on the second hospital day. The patient's level of consciousness returned to normal in tandem with recovery of renal function over several days. There were no residual clinical deficits. After recovery the patient confirmed that he had ingested 3.3 g diphenhydramine in a suicide attempt after conflict with his fiancee. He had been taking the diphen-hydramine tablets for insomnia and had purchased mul-tiple packages from several drugstores. High-performance liquid chromatography (HPLC) analysis of the patient's serum 10 hours after he had ingested the diphenhydramine disclosed a serum concentration of 2.61 mg/mL. (In healthy young adults, the mean maximal serum concentration after ingestion of 50 mg diphenhydramine orally is 82.2 6 31.5 ng/mL [2].) Diphenhydramine is a first-generation antihistamine that can have both excitatory and inhibitory effects on the central nervous system. Its anticholinergic activity can cause autonomic disturbance (3). The previous report of opsoclonus in diphenhydramine poisoning is very similar to ours, in that the patient suffered from opsoclonus, cerebellar ataxia, and mental status changes. The patient confirmed ingestion of 2 g diphenhydramine, and HPLC analysis of the patient's urine confirmed the diagnosis (1). Two reports have described single cases of oculogyric crisis, spasmodic conjugate ocular deviations usually in an upward direction (4,5). Opsoclonus is found mostly in association with viral or paraneoplastic encephalitis, but it may be observed in patients intoxicated with agents such as lithium and organophosphates (6). Lithium may affect the function of glycinergic omnipause neurons, and organophosphate poisoning may affect cholinergic inputs from the peduncu-lopontine to the fastigial nucleus (6). We speculate that the opsoclonus seen in our patient was caused by the anticholinergic activity of diphenhydramine. Interestingly, oculogyric crisis has been reported not only in an overdose of diphenhydramine but also in an overdose of cetirizine, a second-generation antihistamine with anticholinergic effects (7). In light of the fact that diphenhydramine is widely available, clinicians should recognize its potential to cause opsoclonus. Takashi Irioka, MD, PhD Ayaka Yamanami, MD Department of Neurology and Neurological Science Graduate School, Tokyo Medical and Dental University Tokyo, Japan Naoki Uchida, MD, PhD Mariko Iwase, PhD Hajime Yasuhara, MD, PhD Second Department of Pharmacology Showa University School of Medicine Tokyo, Japan Hidehiro Mizusawa, MD, PhD Department of Neurology and Neurological Science Graduate School, Tokyo Medical and Dental University Tokyo, Japan [e-mail] 72 J Neuro-Ophthalmol, Vol. 29, No. 1, 2009 Letters to the Editor J Neuro Ophthalmol, Vol. 29, No. 1, 2009 REFERENCES 1. Hermann DM, Basseti CL. Reversible opsoclonus after diphenhydra-mine misuse. Eur Neurol 2005;53:46 7. 2. Nagai T, Uchida N, Iwase M, et al. A clinical pharmacological study to evaluate the sedative effects of the antihistaminic drug, diphenhydra-mine hydrochloride (Drewell®): Objective evaluation of the sedative effects by analysis of saccadic eye movement. Jpn J Clin Pharmacol Ther 2006;37:55 64. 3. Pragst F, Herre S, Bakdash A. Poisonings with diphenhydramine- a survey of 68 clinical and 55 death cases. Forensic Sci Int 2006;161:189 97. 4. Goetz CM, Lopez G, Dean BS, et al. Accidental childhood death from diphenhydramine overdosage. Am J Emerg Med 1990;8:321 2. 5. Nine JS, Rund CR. Fatality from diphenhydramine monointoxication: a case report and review of the infant, pediatric, and adult literature. Am J Forensic Med Pathol 2006;27:36-41. 6. Diagnosis of nystagmus and saccadic intrusion. In: Leigh RJ, Zee DS. The Neurology of Eye Movements. 4th ed. New York: Oxford University Press; 2006:475 558. 7. Fraunfelder FW, Fraunfelder FT. Oculogyric crisis in patients taking cetirizine. Am J Ophthalmol 2004;137:355 7. See Saw Nystagmus in a Patient with Wallenberg Syndrome See saw nystagmus (SSN), a form of disconjugate nystagmus in which one eye elevates while the other depresses, is most commonly found in patients with large tumors in the region of the diencephalon or mesencephalon (1-3). Trauma, multiple sclerosis, and achiasma may also produce it (3,4). We describe a patient who had SSN as part of a dorsolateral medullary infarct (Wallenberg syndrome) without clinical or imaging evidence of a lesion in the diencephalon or mesencephalon. A 61 year old man reported acute ataxia. Examina-tion disclosed a primary position right hypertropia, left ptosis and miosis, and pendular see saw nystagmus that increased on left gaze. The ascending eye intorted and the descending eye extorted. He also had left facial hypes thesia, right extremity loss of pain and temperature sensation, and gait ataxia. Complete blood count, erythrocyte sedimentation rate, and glucose, urea, and electrolyte levels were normal. Brain MRI showed an acute infarction confined to the left dorsolateral medulla and inferior cerebellum (Fig. 1). Although SSN is considered to be highly localizing to the diencephalon or mesencephalon, there are some exceptions (5). The mechanism of this nystagmus is still not known. Some authors hypothesize a disturbance in visual input because of its frequent association with chiasmal and parasellar lesions (5). But visual loss need not be present, suggesting dysfunction of the rostral brainstem (6), perhaps in the interstitial nucleus of Cajal (INC), a small collection of neurons located adjacent to medial longitudinal fasciculus (MLF) in the midbrain tegmentum (6). Given that our patient had a lesion apparently confined to the medulla and cerebellum the physiopatho logic origin could be related to dysfunction of the vestibular nucleus or the MLF. These pathways have direct connections with the third and fourth cranial nerve nuclei via the MLF and the INC. We suggest that a lesion impairing the function of that circuitry could cause SSN. Jesus Porta Etessam, MD Ignacio Casanova, MD Beatriz Pajuelo, MD Daniella Di Capua, MD Javier del Val, MD Marı´a Eugenia Garc´ıa Garc´ıa, MD Alberto Marcos, MD, PhD FIG. 1. Axial diffusion MRI shows left dorsolateral medullary (small arrow) and inferior cerebellar hemispheric (large arrow) high signal consistent with acute infarction (A) and a normal mesencephalic signal (B). 73 J Neuro Ophthalmol, Vol. 29, No. 1, 2009 Letters to the Editor Neuro ophthalmology Unit and Neurology Department Hospital Universitario Cl´ınico San Carlos Madrid, Spain jporta @yahoo.com REFERENCES 1. Daroff RB. See saw nystagmus. Neurology 1965;15: 874-7. 2. Maddox EE. See saw nystagmus with bitemporal hemianopsia. Proc R Soc Med 1914;7:xii-xiii. 3. Dell'Osso LF, Daroff RB. Two additional scenarios for see saw nystagmus: achiasma and hemichiasma. J Neuroophthalmol 1998;18: 112-3. 4. Sandramouli S, Benamer HT, Mantle M, et al. See saw nystagmus as the presenting sign in multiple sclerosis. J Neuroophthalmol 2005;25:56-7. 5. Liu GT, Volpe NJ, Galetta SL. Eye movement disorders: nystagmus and nistagmoid eye movements. In: Liu GT, Volpe NJ, Galetta SL, eds. Neuro ophthalmology: Diagnosis and Management, 1st ed. Phila-delphia: WB Saunders; 2001:627-50. 6. Miller NR. Nystagmus and related ocular motility disorders. In: Miller NR, ed. Walsh and Hoyt's Clinical Neuro Ophthalmology, 4th ed. Baltimore: Williams & Wilkins; 1982:907-8. Another Case of Paroxysmal Tonic Downgaze in Infancy Two years ago, Wolsey and Warner (1) reported in this journal on two healthy infants with brief episodes of downgaze followed by abnormal body movements. They called this condition ‘‘paroxysmal tonic downgaze'' and considered it idiopathic and transient. We extend their report by describing a 2 month old healthy boy presenting with an episodic downward gaze disturbance (Fig. 1). Born at term after an uneventful delivery and normal development, he was transferred for possible ‘‘seizures'' from another hospital. The spells had started 7 days before presentation, coincident with a diagnosis of a new upper respiratory tract infection. We observed many spells per day that lasted between 10 and 90 seconds without any impairment in consciousness and seemed to occur more frequently when he was supine or upon awakening but never in an upright position or during sleep. They did not appear to follow touching or shaking. Longer spells were associated with stiffening of the right upper extremities. Ophthalmologic examination disclosed that he fixed and followed equally with each eye. He had normal alignment and full extraocular movements without nystag-mus. Neurologic examination showed slightly reduced muscle tone but normal muscle strength and deep tendon reflexes. There was no ataxia. 74 FIG. 1. Downward eye deviation in a 2 month old boy. The downward eye deviation occurred many times per day, lasted from 10 to 90 seconds, and resolved spontaneously within 3 months. The child underwent MRI and an electro-encephalogram (EEG) because of a report of hydrocephalus and seizures in very similar downgaze episodes in children aged 2 to 8 months (2) who later showed severe developmental disabilities. Results of these studies were normal. Because we could not entirely exclude opsoclonus myoclonus syndrome, we undertook evaluation for neuro blastoma with ultrasound of the abdomen, urine for vanillylmandelic acid levels, and iodine 131 metaiodoben zylguanidine (MIBG) scanning (3). Results of all studies were negative. The episodes began to decrease in frequency spontaneously 1.5 months after they began and resolved within 3 months. He did not develop any neurologic problems in the subsequent 18 months and has had normal development except for a slight delay in expressive language and a mild attention deficit. The pathogenesis of this transient gaze disturbance is not understood. Some observers have hypothesized that it may be the result of immature myelination of the corticomesencephalic vertical gaze pathways (4). Its transient nature, especially in older infants, may result from temporary failure of cortical compensation when a stressor such an illness is present (5). Our experience reinforces the idiopathic and transient nature of this condition. Even so, this manifestation is frightening. Because more serious conditions cannot be entirely excluded, imaging and an EEG cannot be avoided. q 2009 Lippincott Williams & Wilkins Letters to the Editor J Neuro-Ophthalmol, Vol. 29, No. 1, 2009 Meropi Tzoufi, MD Polyxeni Sixlimiri, MD Alexandros Makis, MD Antigone Siamopoulou-Mavridou, MD Child Health Department Medical School of the University of Ioannina Ioannina, Greece E-mail: [e-mail] REFERENCES 1. Wolsey DH, Warner JE. Paroxysmal tonic downgaze in two healthy infants. J Neuroophthalmol 2006;26:187-9. 2. Yokochi K. Paroxysmal ocular downward deviation in neurologically impaired infants. Pediatr Neurol 1991;7:426-8. 3. Pranzatelli MR. The neurobiology of the opsoclonus-myoclonus syndrome. Clin Neuropharmacol 1992;15:186-228. 4. Walsh FB, Hoyt WF. Clinical Neuro-ophthalmology, Vol 1. 3rd ed. Baltimore: Williams & Wilkins; 1969:230. 5. Ouvrier R, Billson F. Paroxysmal tonic upgaze of childhood- a review. Brain Dev 2005;27:185-8. Leber Hereditary Optic Neuropathy Associated with Malabsorption Syndrome After Bariatric Surgery We report a patient who developed bilateral visual loss from Leber hereditary optic neuropathy (LHON) in conjunction with chronic malabsorption consequent to bariatric surgery. A 31-year-old man reported visual loss in his left eye and, 2 weeks later, in his right eye. His vision gradually worsened down to finger counting at a distance of 1 m, and he was admitted to the hospital for study. He had undergone vertical banded gastroplasty for morbid obesity 3 years earlier. He smoked 10 cigarettes/day and drank a few alco-holic drinks on weekends. Past ocular history was negative. Family history was remarkable for a maternal cousin with a history of unexplained poor vision since childhood. On our examination, visual acuity was 20/40 in the right eye and 20/200 in the left eye. There was a dense central scotoma in the visual field of the left eye and a pale optic disc in that eye. There was an afferent pupil defect on the left. No other ocular findings were detected, and results of the neurologic examination were unremarkable. Results of extensive hematologic, serologic, and cerebrospinal fluid studies were all normal or negative except for decreased serum levels of vitamin E at 3.4 mg/mL (normal range 5-20 mg/mL), borderline serum levels of vitamin B12 and folate (253 pg/mL and 3.6 ng/mL, respectively), and increased mean corpuscular volume at 101 fL. Results of CT and MRI of the brain and orbits were normal. Pattern-reversal visual evoked potentials revealed marked bilateral delay with P100 latencies of 130.8 ms from the right eye and 156.3 ms from the left eye. The patient received treatment with 1,000 mg/day methylprednisolone intravenously for 5 days, as well as oral vitamin B complex and vitamin E. There was no improve-ment in vision during his hospitalization. Genetic testing, performed at Public Foundation of Genomic Medicine (Santiago de Compostela, Spain), showed a homoplasmic mitochondrial DNA (mtDNA) mutation at position 11778A, confirming the clinical diag-nosis of LHON. On a 10-month follow-up, clinical examinations showed no substantial changes. We have described a young man with a LHON mtDNA mutation and a history of moderate alcohol and tobacco abuse who developed subacute bilateral optic neuropathy in the setting of chronic malabsorp-tion (multiple vitamin deficiency) induced by bariatric surgery. Epigenetic factors are reported to contribute to the clinical expression of LHON mtDNA mutations, including tobacco smoking, alcohol consumption, uncontrolled diabetes, ethambutol use, and antiretroviral therapy (1). There are similarities between the optic neuropathies of LHON, vitamin B1 deficiency, and vitamin B12 deficiency, suggesting that abnormalities of adenosine triphosphate levels might be the common underlying pathogenetic mechanism (2). In our patient, tobacco smoking and alcohol consumption may have contributed. Visual loss began after bariatric surgery, perhaps in the context of malabsorption. Asymptomatic 11778 mtDNA LHON carriers fre-quently show manifestations of optic nerve impairments in relation to environmental factors (3), just as mutations in the 12S rRNA gene of the mitochondrial genome increase susceptibility to the ototoxicity of aminoglycoside anti-biotics (4). Three cases of LHON in subjects who also had low serum vitamin B12 levels at the time of symptom onset have recently been reported (5). Taken together, these observations suggest that optic neuropathy in patients carrying a primary LHON mtDNA mutation may be precipitated by vitamin deficiency. Patients who have undergone bariatric surgery show multiple biochemical abnormalities consistent with malab-sorption, including low serum levels of vitamin B12, vitamin D, vitamin E, calcium, copper, or zinc. Some patients develop encephalopathy, optic neuropathy, pos-terolateral myelopathy, acute polyradiculoneuropathy, and polyneuropathy. Perhaps a positive family history of visual loss should prompt mtDNA investigations before bariatric surgery is considered. 75 J Neuro Ophthalmol, Vol. 29, No. 1, 2009 Letters to the Editor Diego Santos Garc´ıa, MD, PhD Javier Abella, MD Section of Neurology Hospital A. Marcide Ferrol, Spain Begona De Domingo, MD Service of Ophthalmology Hospital A. Marcide Ferrol, Spain Raul de la Fuente Fernandez, MD Section of Neurology Hospital A. Marcide Ferrol, Spain [e-mail] REFERENCES 1. Carelli V, Ross Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res 2004;23:53-89. 2. Rizzo JF 3rd. Adenosine triphosphate deficiency: a genre of optic neuropathy. Neurology 1995;45:11-6. 3. Sadun AA, Salomao SR, Berezovsky A et al. Subclinical carriers and conversions in Leber hereditary optic neuropathy: a prospective psychophysical study. Trans Am Ophthalmol Soc 2006;104:51-61. 4. Guan MX, Fischel Ghodsian N, Attardi G. Biochemical evidence for nuclear gene involvement in phenotype of non syndromic deafness associated with mitochondrial 12S rRNA mutation. Hum Mol Genet 1996;5:963-71. 5. Pott JW, Wong KH. Leber's hereditary optic neuropathy and vitamin B12 deficiency. Graefes Arch Clin Exp Ophthalmol 2006;244:1357-9. Perinatal Head Tilt in Congenital Superior Oblique Palsy Congenital superior oblique palsy is often misdiag nosed as congenital muscular torticollis in the young child with a persistent unilateral head tilt (1,2). One of the distinguishing features of these conditions is said to be the later time of onset of the torticollis in congenital superior oblique palsy (1,2). However, we recently examined a patient who used a compensatory head tilt for binocular fusion almost from birth, demonstrating that a perinatal head tilt can result from congenital superior oblique palsy. A 2½ year old girl was referred for possible strabismus. According to her parents, she had maintained a large right head tilt since birth. An orthopedist had diagnosed congenital muscular torticollis and treated her with passive stretching exercises without improvement. She was neurodevelopmentally normal and had no family history of torticollis or strabismus. FIG. 1. Postcontrast T1 coronal MRI shows reduced bulk of the left superior oblique tendon (arrow, compare with normal right side), consistent with hypoplasia. On our examination, she had normal optokinetic responses and pupillary responses to light, and no fixational preference with either eye. She had no restriction to passive neck rotation, but maintained a right head tilt of 25 degrees with a small right head turn. She had 6 prism diopters of left hypertropia that increased to 30 prism diopters in right gaze and to 12 prism diopters in left head tilt. She had no detectable hyperdeviation in left gaze or in right head tilt. Retinal examination showed 3+ extorsion of the left eye. Brain and orbit MRI showed selective hypoplasia of the left superior oblique muscle (Fig. 1). A left inferior oblique muscle recession produced resolution of the torticollis. A review of old photographs revealed an interesting and unrecognized phenomenon. Beginning at 2 weeks of age, she always leaned to the right side when sitting or being held, allowing gravity to tilt her head and trunk to the right (Fig. 2). She maintained this consistent body posture until 6 months of age, at which time her trunk straightened and her head remained tilted (Fig. 2). She also maintained a slight right head turn and a gaze preference to the left. While awake and during sleep, her head tilt resolved in the supine position. For confidentiality reasons, her parents requested that these photographs not be published. Congenital muscular torticollis is said to be present from birth or shortly thereafter, whereas ocular torticollis is said to appear later, when the child develops sufficient head control to maintain an abnormal head position for fusion (1,2). Duke Elder and Wyber (1) and von Noorden (2) stated that the head tilt associated with congenital superior oblique palsy may not develop until 18 months of age. Our patient belies this clinical axiom by showing that congenital superior oblique palsy can be associated with a head tilt that develops within the first month of life. In the 76 q 2009 Lippincott Williams & Wilkins Letters to the Editor J Neuro-Ophthalmol, Vol. 29, No. 1, 2009 FIG. 2. Graphic representation of photographs of patients taken in seated position at age 3 weeks (A), 3 months (B), and 6 months (C). absence of head control, our patient allowed gravity to passively tilt her body in the compensatory direction to optimize utricular input for vertical fusion. By 6 months of age, head control had become established, allowing her to straighten her trunk while maintaining her head in its tilted and slightly turned position. Mocan et al (3) documented a right gaze preference in a 3-week-old infant with transient left sixth cranial nerve paresis, suggesting that active binocular visual processing was already producing a robust drive to fuse. This patient demonstrates that infants with congenital superior oblique palsy can use gravitational body tilt to compensate for vertical diplopia shortly after birth. For this reason, superior oblique palsy should not be ruled out as the cause of a history of unidirectional head tilt that begins within the first month of life. Michael C. Brodsky, MD Virginia Karlsson, CO Department of Ophthalmology Mayo Clinic Rochester, Minnesota [e-mail] REFERENCES 1. Duke-Elder S, Wybar K. System of Ophthalmology, Vol VI: Ocular Motility and Strabismus. St. Louis: CV Mosby; 1973:681. 2. von Noorden GK. Binocular Vision and Ocular Motility: Theory and Management of Strabismus. 5th ed. St. Louis: CV Mosby; 1996:398. 3. Mocan MC, Wright KW, Salvador MG. Evidence of binocular fusion in a 3-week-old infant with transient abducens nerve paresis. JAAPOS 2007;11:199-200. 77