Paroxysmal Tonic Upgaze in Children Three Case Reports and a Review of the Literature

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Paroxysmal Tonic Upgaze in Children

Three Case Reports and a Review of the Literature

Ayse Kartal, MD

Background:In clinical practice, nonepileptic paroxysmal events during infancy and childhood are common reasons for parents and caregivers to seek for medical advice. These events are mostly unrecognized and consid-ered as an epileptic seizure because of the clinical features resembling an epileptic seizure. Paroxysmal tonic upgaze, which consists of recurrent ep-isodes of sustained upward deviation of the eyes and incomplete downward saccades, and normal horizontal eye movements without impairment of consciousness, is a diagnostic challenge for the pediatrician and pediatric neurologist. In general, the entity was defined as an apparently benign phe-nomenon with normal investigations and eventual complete resolution of the symptoms, although some authors reported on patients with associated neurologic signs, such as ataxia, developmental delay, and abnormal brain magnetic resonance imaging finding.

Methods:The patients were 3 children (1 boy and 2 girls) who were between 5 and 18 months old experiencing rapid ocular movements with sustained conjugate upward deviation of the eyes. Their attacks, which were recorded using a video or electroencephalogram system, were also investigated comprehensively, including neurologic examination, electroen-cephalograms, brain magnetic resonance imaging, and metabolic tests. Par-oxysmal tonic upgaze attacks have decreased in number or disappeared in 2 patients, but 1 patient exhibited mild abnormalities on magnetic resonance imaging and had relatives with epilepsy.

Conclusions:In conclusion, paroxysmal tonic upgaze is an apparently benign phenomenon with unclear pathophysiology of various proposed mechanisms such as genetic predisposition, immaturity of the brain stem, neurotransmitter depletion, or immune dysregulation. It is important to rec-ognize the clinical presentation of paroxysmal tonic upgaze and distinguish the disorders from epilepsy for deciding the treatment and prognosis of the patients.

Key Words: paroxysmal tonic upgaze, nonepileptic paroxysmal events, epileptic seizures

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distinct condition. The disorder usually begins in the infantile or early childhood, and it is characterized by sudden ocular movements with sustained upward deviation of the eyes, incomplete downward saccades, and normal horizontal eye movements. Consciousness is not affected during episodes, but sometimes accompanied by

varying degrees of ataxia. The duration and frequency of episodes are variable, ranging from few minutes to hours and days. These ep-isodes show diurnal rhythm and are frequently exacerbated by inter-current febrile illness or vaccination and fatigue and are relieved by sleep.

In these patients, findings from neurologic examination, electroencephalogram (EEG), neuroimaging, and laboratory and neurophysiological investigations frequently are normal. Never-theless, some studies have reported on patients with other associ-ated neurologic symptoms, such as ataxia, developmental delay, nystagmus, and abnormal magnetic resonance imaging.2

The etiology of PTU is still unclear; some studies have pro-vided evidence for a genetic basis contribution to the pathogene-sis, but the involved genes have not been found.

Because we have made an extensive literature review, the paucity of cases in the literature precludes reliable clinical and prognostic data. The aims of our case series are to review the reported cases, present 3 new cases, and discuss the features of PTU.

CASE 1

A 5-month-old boy was referred to our neurology department for evaluation of episodes of sudden upward deviation of the eyes. The patient was the only child of first-degree consanguineous Turk-ish healthy parents. He was born at term after uneventful gestation. There was a family history of cerebral palsy from the maternal side. Early developmental milestones were normal; he achieved head control at 2 months old.

The paroxysmal episodes had started 5 days before admis-sion and manifested with conjugate tonic upward eye deviation lasting approximately 10 to 20 seconds and associated with neck flexion. According to her parents, these episodes were exacer-bated by fatigue and relieved by sleep. Neurologic examination showed normal cranial nerve examination results, normal tone, strength, and deep tendon reflexes with bilateral flexor plantar re-sponse. No ataxia or nystagmus was observed.

The findings from the metabolic an neuroradiological inves-tigations and from EEG were normal. Typical episodes for PTU were observed during the hospitalization, and thereafter, the diag-nosis of PTU was made (see Appendix A, video 1, http://links. lww.com/PEC/A211).

At present, tonic upgaze episodes have disappeared after 6 months since its onset without any treatment.

CASE 2

A girl aged 6 months was referred because of attacks of con-jugate superior deviation of the eyes. The patient is the second child of nonconsanguineous healthy parents. She was born at term by spontaneous normal delivery. The antenatal period was unevent-ful. The patient had no family history of neurologic illnesses and de-velopmental disabilities. Her parents noticed her first abnormal eye movements lasting for 10 to 30 seconds that started 2 weeks before admission when she had a febrile illness; it was accompanied by down-beating nystagmus. There was no abnormality of horizontal

From the Division of Child Neurology, Selçuk University Faculty of Medicine, Alaeddin Kampusu, Selçuklu/Konya, Turkey.

Disclosure: The authors declare no conflict of interest.

Ethical Approval: Informed consent was obtained from the patient's parents to publish this report. The parents gave written permission for the publication of the video.

Reprints: Division of Child Neurology, Selçuk University Faculty of Medicine, Alaeddin Kampusu, Selçuklu/Konya, Turkey

(e_{‐mail: kartalays@gmail.com).}

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.pec-online.com). Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0749-5161

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eye movements except in upgaze. Episodes were more pronounced before sleep and disappeared during sleep.

Neurologic examination finding was normal. Laboratory in-vestigations showed normal values of blood counts, chemistry, elec-trolytes, urine organic acids, tandem mass, plasma lactate, pyruvate, and thyroid function tests. Evaluation included normal EEG and brain magnetic resonance imaging results.

CASE 3

An 18-month-old girl was admitted to pediatric neurology department with a history of recurrent afebrile seizures, which were first seen at 2 months of age. Paroxysmal conjugate upward deviation of the eyes accompanied by these seizures lasted for 1 year. She was born at term by spontaneous normal delivery. The antenatal period was uneventful. The patient had no family history of a movement disorder or a neurologic disease. She had delayed developmental milestones, that is, head control at 5 months and sit-ting at 14 months, and she could still walk without support at the time of referral. Her first words happened at the age of 14 months. Her parents first noticed abnormal eye movements at 6 months of age. These attacks manifested as conjugate upward eye devia-tion, lasting for 10 to 15 seconds and appearing multiple times daily. Her parents also reported the frequency of the episodes in-creasing significantly while the patient had constipation or febrile illness, or was tired.

Results from the neurologic and ophthalmologic exami-nations were normal aside from her gross motor delay and diffuse hypotonia.

An extensive evaluation showed normal results, except for low levels of B12(<150 N: 300–960 pg/mL). An EEG without

video monitoring was performed during which the patient had stereotypical eye movements. These events did not have associ-ated epileptiform activity in the EEG record. Brain magnetic res-onance imaging revealed enlargement of the subarachnoid spaces and hypomyelination.

In light of these findings, a diagnosis of PTU was made, and she was started on intramuscular B12therapy. The episodes were

not observed after initiation of B12treatment. DISCUSSION

Paroxysmal tonic upgaze of childhood was originally de-scribed by Ouvrier and Billson1in 1988 as apparently benign dis-ease. During the past years, the classic phenotype of this disease, in addition to originally reported, has broadened significantly. Also, the following clinical findings have been described:

1. Usually onset in early to mid infancy

2. The abnormal ocular movements characterized by an episodic sustained conjugate upward deviation of the eyes, with neck flexion compensating for the abnormal eye position, and nor-mal horizontal eye movements

3. Frequent exacerbation with febrile illnesses, prolonged wake-fulness, fatigue, and stressful events

4. Frequent relief by sleep

5. Eventual improvement and recovery

6. Normal results from the metabolic, EEG, and neuroradiological investigations

7. An impaired ability to coordinate movements3

The incidence of PTU is unknown. Paroxysmal tonic upgaze is probably not well recognized by clinicians, and it is probably underdiagnosed. Hayman et al4reported 16 cases, during an 8-year period arising in a population of approximately 4 million people. In their review, the age at onset of PTU varied between 1 week and

26 months (mean, 5.5 months), whereas in the series of Salmina et at,3reported age of onset varied between 2 weeks and 90 months. Among published cases, a small predilection for the male sex was reported.

The duration and frequency of episodes are variable, with time gradually decreasing until complete cessation. Verrotti et al5reported that tonic upgaze episodes stopped between 1 and 4 years, without any therapy and without any change in psychomotor development. The pathophysiological basis of PTU is not completely un-derstood. Several mechanisms have been proposed, including a genetic predisposition, immaturity of the upper dorsal brainstem, the depletion of a neurotransmitter in the dorsal brain, or unrecog-nized channelopathy and immune dysregulation.2It is likely that several of these factors need to be included for PTU to develop. Nevertheless, there are clues to support the hypothesis that genetic factors and channelopathy contribute to susceptibility. First, there is the presence of familial cases suggesting an autosomal recessive inheritance. Second, some PTU cases have been associated with CACNA1A mutation. The study by Blumkin et al6_{reported that}

heterozygous mutations in the ion transport domains and the voltage-dependent channel on CACNA1A gene were detected in patients with PTU. The authors hypothesized that this mutation may represent a genetic predisposition for PTU. CACNA1A gene has already been associated with susceptibility to several complex diseases, such as episodic ataxia type 2 and paroxysmal vertigo.7 However, a history of febrile illness or immunization before onset in some patients may suggest an association with immu-nologic events. Furthermore, fatigue or stressful events such as constipation as seen in the third case were often followed by an increased frequency of episodes of upward deviation of the eyes. On the other hand, these episodes were relieved by sleep, and with time, the duration and frequency of the tonic upward gaze episodes decreased.4–6

Interestingly, we found low levels of vitamin B12 in one

of our patients, and this has not been previously reported in the lit-erature. Typical neurologic symptoms in infancy are irritability, weakness, developmental delay, and failure to thrive.8_{It is well}

known that vitamin B12plays an important role in the metabolism

of the nervous system, although its exact role in normal and path-ologic conditions is poorly understood. Vitamin B12deficiency

leads to abnormal myelination or demyelination, imbalance of neurotrophic and neurotoxic cytokines, accumulation of lactate in brain cells, and impaired neurotransmission. Our patient had developmental delay and hypomyelination on brain magnetic res-onance imaging. Therefore, we suggested that B12deficiency may

have contributed to the formation of the PTU.

In the present study, age at onset, exacerbation with fatigue, and relief with sleep were similar to the findings in previous re-ports. Electroencephalogram finding was normal in all patients, whereas only 1 patient had an abnormal brain magnetic resonance imaging finding, as described in Hayman et al and Sguie et al.4–7,9 In patients with PTU, some abnormal neuroimaging findings such as periventricular leukomalacia, delayed myelination, or struc-tural abnormalities have been reported. In a recent study published by Salmina et al,3_{PTU in healthy children was reviewed, and most}

of the patients had normal neuroimaging findings.

Although 2 of the original patients eventually showed cogni-tive impairment, most published cases had normal neurocognicogni-tive development.1–3Furthermore, inability to coordinate movements was noted in some cases.

Some treatment regimens including antiepileptic agents and levodopa have been suggested. A noticeable improvement was noted in some patients with levodopa, but there was no improve-ment with antiepileptic agents. However, routine levodopa treat-ment is not recommended.3

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In 2 of our patients, one had low level of vitamin B12,

hy-droxocobolamin, and the other did not receive any treatment; how-ever, complete recovery was seen in both.

In conclusion, PTU can be considered as an age-related form of paroxysmal dyskinesia beginning in the first years of life that, generally, remits spontaneously within months or a few years. The outcome was excellent in most children, although persistent fine motor and neurocognitive impairment has been described.

ACKNOWLEDGMENT

The author wish to thank Alexis K. Okoh for editing assistance.

REFERENCES

1. Ouvrier RA, Billson F. Benign paroxysmal tonic upgaze of childhood. J Child Neurol. 1988;3:177_–180.

2. Ouvrier R, Billson F. Paroxysmal tonic upgaze of childhood: a review. Brain Dev. 2005;27:185–188.

3. Salmina C, Taddeo I, Falesi M, et al. Paroxysmal tonic upgaze in normal children: a case series and a review of the literature. Eur J Paediatr Neurol. 2012;16:683–687.

4. Hayman M, Harvey AS, Hopkins IJ, et al. Paroxysmal tonic upgaze: a reappraisal of outcome. Ann Neurol. 1998;43:514–520.

5. Verrotti A, Trotta D, Blasetti A, et al. Paroxysmal tonic upgaze of childhood: effect of age-of-onset on prognosis. Acta Paediatr. 2001;90:1343_–1345. 6. Blumkin L, Leshinsky-Silver E, Michelson M, et al. Paroxysmal tonic

upward gaze as a presentation of de-novo mutations in CACNA1A. Eur J Paediatr Neurol. 2015;19:292_–297.

7. Roubertie A, Echenne B, Leydet J, et al. Benign paroxysmal tonic upgaze, benign paroxysmal torticollis, episodic ataxia and CACNA1A mutation in a family. J Neurol. 2008;255:1600–1602.

8. Dror DK, Allen LH. Effect of vitamin B12deficiency on neurodevelopment

in infants: current knowledge and possible mechanisms. Nutr Rev. 2008;66: 250–255.

9. Sugie H, Sugie Y, Ito M, et al. A case of paroxysmal tonic upward gaze associated with psychomotor retardation. Dev Med Child Neurol. 1995;37: 362–365.

Pediatric Emergency Care • Volume 35, Number 4, April 2019 Paroxysmal Tonic Upgaze in Children

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