Abstract
To The Editor:
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Children with developmental delay and other neurological disorders often develop nocturnal enuresis (Järvelin 1989; Simonoff et al. 2008; Zhao et al. 2009; Gor et al. 2012; Nappo 2012). The treatment of enuresis in these patients is more difficult because of psychological and behavioral changes. Pharmacological intervention using desmopressin and anticholinergic drugs is questionable, because of the mixed outcomes from the treatment (Naitoh et al. 2005; Yucel et al. 2011; Gor et al. 2012), as well as severe side effects (Müller et al. 2004; Gish et al. 2009; Friedman et al. 2011).
Here, we report a case of disappearance of nocturnal enuresis in an 18-year-old patient with childhood autism after oral application of a low dose of methylcobalamin. The patient was enrolled in the study to examine the effect of methylcobalamin on the psychobehavioral profile in patients with autism.
Case Report
We present the case of an 18-year-old male (J.N.) with the primary diagnosis childhood autism (F84.0, from the International Statistical Classification of Diseases and Related Health Problems [ICD], 10th revision, Classification of Mental and Behavioral Disorders) (World Health Organization [WHO] 2003). The assessment was conducted by a pediatric and adolescent clinical and educational psychologist, using objective diagnostic methods (Autism Diagnostic Interview-Revised [ADI-R] [Rutter et al. 2003] and Childhood Autism Rating Scale [2-CARS] [Schopler et al. 2010]). Monosymptomatic enuresis nocturnal was diagnosed in the early years of the patient's life and was unsuccessfully treated in childhood with high doses of oxybutynin (5 mg/day). The patient did not have any bowel or other gastrointestinal problems typical of autism (Erickson et al. 2005; Levy et al. 2009).
Prenatal, birth, and early life history
J.N. was the second child of a 36-year-old mother and a 38-year-old father. No pregnancy or childbirth complications were reported. While in utero, he was diagnosed with hypertrophy of the renal pelvis. The first symptoms of autism were observed between the 1st and 2nd years of life, whereas childhood autism was diagnosed after his second birthday. At this age, stereotyped movement (e.g., rocking from foot-to-foot, constant turning of cord in his hand), failure to develop speech, inability to individually perform everyday activities (e.g., to reach out for a bottle or biscuit), and lack of response to stimuli were observed.
Therapy management
During the first 4 years of the patient's life, he used the antiasthmatic medication, cromolyn sodium (Intal), which was probably the reason for severely (permanently) damaged teeth. From the ages of 1–6 years, atypical skin peeling on his palms was treated with homeopathic drugs. From 8 years of age, the patient was put on an experimental gluten-free, casein-free diet, with no change in symptoms. The diet was therefore stopped in September 2012, when he began to eat dairy products again. He was treated with oxybutynin (Ditropan; 5mg/day) during the period 2003–2004. Since 2007, he has been taking herbal drops (Korolen), which contain herbal extracts, essential oils, and biocomponents.
On February 6, 2012, he was enrolled in a study with autistic children and adolescents, in which the effect of long-term administration of a low methylcobalamin dose on psychobehavioral and biochemical profiles was examined (manuscript in preparation). Methylcobalamin was administered at a dose of 500 μg in 5 mL volume (in syrup form) once a day after the first meal. The patient attended a special care unit on a regular every workday basis where his psychobehavioral status was under constant assessment by specialized psychologists.
Disappearance of nocturnal enuresis during the methylcobalamin treatment
Nocturnal enuresis occurred in the patient with nightly frequency; enuresis was not present during the day. Within the period of treatment with low doses of methylcobalamin, a progressive decrease in the frequency of nocturnal enuresis was observed by his parents. During the 6th week, the enuresis stopped completely and was absent in highly familiar environments (home) and also in less familiar ones (in the house of his grandparents). Nocturnal enuresis reappeared once the therapy was discontinued (days 230–244), but with lower frequency. Restarting the methylcobalamin treatment led to the disappearance of the nocturnal enuresis again.
Psychobehavioral changes during the methylcobalamin treatment
Based on everyday observations by psychologists, typical behavioral features of a pervasive developmental disorder were still present in the patient, including impaired social interaction and communication, and limited interests. However, increased tolerance and interest in social situations and familiar environments were observed. Moreover, a slight improvement was observed in the ability to self-perform everyday tasks. On the other hand, increased motor stereotypy and hyperactive behavior was observed within 100 days of the treatment, and aggressive behavior and anger, without any clear reason, was noticed 230 days after treatment was initiated.
Based on the parents' observations, the patient started to show more interest in spending his time in rooms that he used to avoid before (e.g., the living room). Moreover, he started to pay attention to objects and experiences he had been indifferent to before, for example, noticing a slipper that had fallen under the sofa, or watching TV for 5 minutes.
Biochemical changes following the methylcobalamin treatment
Basic biochemical parameters related to the oxidative stress (reduced form of glutathione [GSH]; oxidated form of glutathione [GSSG]; glutathione redox status; homocysteine and cystine; and vitamin B12) were examined by high-performance liquid chromatography (HPLC) in plasma before treatment (d0), on day 100 (d100), and on day 200 (d200) of the treatment. As for the glutathione profile (Table 1), the glutathione redox status (calculated as GSH/GSSG) decreased at d100 and increased at d200, relative to d0. This was because of the lower GSH level at d100 and increased GSH and GSSG levels at d200. Plasma concentrations of the other followed parameters were within the physiological values in all collected samples (data not shown).
Plasma obtained before treatment (d0), at day 100 of the treatment (d100), and at day 200 of the treatment (d200) was analyzed by high-performance liquid chromatography (HPLC). The levels of the reduced form (GSH) and the oxidized form (GSSG) of glutathione were determined, and glutathione redox status was calculated (GSH/GSSG values).
Discussion
Currently, there is no effective treatment for autism; however, multiple therapeutic approaches were suggested in the past (Rossignol 2009; (Kumar et al. 2012; Benvenuto et al. 2013). A pilot study with intramuscularly administered high doses of methylcobalamin, in children with autism, suggested a possible benefit for their overall psychobehavioral profile (Bertoglio et al. 2010). In response to this study, we performed a more detailed evaluation of the impact of long-term low doses of methylcobalamin on pediatric and adolescent patients with autism. During the study, we observed a cessation of nocturnal enuresis in an 18-year-old patient, which coincided with treatment. Similar observations were made in two other subjects, but because of their young age (3 and 5 years old) it was difficult to conclude that the change was caused by the treatment, as nocturnal enuresis may be classified only in patients >5 years of age.
As the observations by the psychologist and parents suggested an increased awareness of the surrounding environment, it is possible that the positive effect was caused by awareness of a full bladder. The mechanism of action of methylcobalamin is poorly understood so far, although a change in oxidative status (James et al. 2009; Bertoglio et al. 2010) and improved methylation capacity (James et al. 2004) were proposed in the past. In our subject, we also observed positive changes in glutathione redox status. Nevertheless, it is difficult to draw a clear link between changed oxidative status and/or methylation capacity and awareness of a full bladder, or other effects by which nocturnal enuresis may be explained.
In our case study, none of unwanted effects were observed during treatment with methylcobalamin; however, some changes in psychobehavioral characteristics (i.e., a propensity toward aggression and anger for no obvious reason) were reported at day 230 of the treatment, or thereabouts, which might pose a serious problem to the patient and his environment.
However, we do believe that methylcobalamin treatment may be a possible therapeutic approach, although at this point more evidence for its efficacy and safety is needed.
Footnotes
Acknowledgments
We thank Dr. Evan D. Paul (Integrative Physiology and Center for Neuroscience, University of Colorado, Boulder, CO), and Oľga Holá and Darina Kližanová (Department of Languages, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic) for the proofreading of the manuscript.
Disclosures
No competing financial interests exist.