Reversal of Stroke-Like Episodes With L-Arginine and Meticulous Perioperative Management of Renal Transplantation in a Patient With Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome. Case Report.

Mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder with recurrent non-arterial distribution stroke-like episodes (SLEs). A 17 yr old boy with MELAS (m.3243A>G tRNALeu(UUR)) presented with SLEs at ages 8 and 10 yrs. At 11 yrs, he suffered a third SLE involving left parietotemporal lobes with dense right hemiplegia and aphasia persistent for 1 week without improvement. On high dose IV L-Arginine (L-Arg) (0.5 g/kg/day divided TID) he had rapid recovery within 48 hours and was rapidly weaned. With emesis of oral L-Arg, his SLE recurred and he was again treated with high dose IV L-Arg with similar rapid recovery and discharged on a slow wean over 6 wks to 0.1 g/kg/day. On maintenance L-Arg he suffered only 2 SLEs at ages 13 and 16 yrs; both resolved rapidly with high dose IV L-Arg without recurrence during a slow wean to maintenance. His phenotype included seizures, ptosis, ophthalmoplegia, facial diplegia, sensorineural hearing loss, ataxia, myopathy, exercise intolerance, peripheral sensorimotor neuropathy, hypertrophic cardiomyopathy, hypertension, and failure to thrive. At 16 yrs he developed end-stage renal disease, due to MELAS, requiring hemodialysis and at 17 yrs he underwent cadaveric renal transplantation. His peri-operative protocol included strict maintenance of perfusion, oxygenation, normothermia, biochemical homeostasis and serum arginine concentrations during which time there were no neurologic decompensations. He was transitioned to oral L-citrulline maintenance therapy which maintained higher serum arginine concentrations with better tolerance. He had no SLEs or seizures in the ensuing 2 yrs.

Dystonia in RNA Polymerase III-Related Leukodystrophy.

OBJECTIVES: To identify the prevalence of dystonia in a RNA Polymerase III (POLR3)-related leukodystrophy patient cohort and to further characterize their dystonic features. BACKGROUND: POLR3-related leukodystrophy is a hypomyelinating leukodystrophy characterized by neurological and non-neurological features. Dystonia remains a challenging and under-recognized feature. METHODS: A retrospective chart review was performed in a cohort of 20 patients for whom videos of a standardized neurological examination were available. Patients were recruited at the Montreal Children's Hospital of the McGill University Health Center and the Myelin Disorders Bioregistry Project. Families were consented at the initial assessment and the following data was recorded: age and symptoms at clinical presentation, investigations, causal gene and mutation(s), type and severity of dystonia, and treatment response when needed. Standardized examination videos were reviewed by three independent reviewers and scored using the Global Dystonia Scale. RESULTS: 10 males and 10 females were included in this study; 12/20 had POLR3A mutations, while 8/20 had POLR3B mutations; 19/20 patients had documented dystonia, with 3/19 requiring therapy. There was a good response in two patients to a single agent, and a poor response in one patient to three agents; the majority had mild-to-moderate multifocal dystonia without a functional impact. CONCLUSIONS: Dystonia is a common, yet underdiagnosed, slowly progressive manifestation of POLR3-related leukodystrophy, and in most cases has limited-to-no functional impact. When treatment is needed, good response to typically used medication may occur. Further studies are needed to assess evolution of dystonia over time, patients' functional outcome, and response to therapy (when needed).

Two Novel KCNQ2 Mutations in 2 Families With Benign Familial Neonatal Convulsions.

Benign familial neonatal convulsion is a rare autosomal dominant inherited epilepsy syndrome characterized by unprovoked seizures in the first few days of life, normal psychomotor development, and a positive intergenerational family history of neonatal seizures. Over 90% of the affected individuals have inherited causal mutations in KCNQ2, which encodes for the potassium voltage-gated channel subfamily Q, member 2. Mutations in KCNQ2 are also associated with a severe neonatal encephalopathy phenotype associated with poor seizure control and neurodevelopmental deficits. The authors report the clinical presentations, response to medication, and intrafamilial phenotypic variability in 2 families with benign familial neonatal convulsions, carrying previously unreported heterozygous missense mutations, c.1066C>G (p.Leu356Val) and c.1721G

Intraventricular hemorrhage in asphyxiated newborns treated with hypothermia: a look into incidence, timing and risk factors.

BACKGROUND: Intraventricular hemorrhage (IVH) is uncommon in term newborns. Asphyxia and hypothermia have been mentioned separately as possible risk factors of IVH, since they might cause fluctuations of cerebral blood flow. The aim of this study was to assess the incidence, the timing, and the risk factors of intraventricular hemorrhage (IVH) in term asphyxiated newborns treated with hypothermia. METHODS: We conducted a prospective cohort study of all term asphyxiated newborns treated with hypothermia from August 2008 to June 2013. The presence or not of IVH was assessed using brain magnetic resonance imaging (MRI) performed after the hypothermia treatment was completed or using head ultrasound during the hypothermia treatment. For these newborns, to determine the timing of IVH, we retrospectively reviewed if they had other brain imaging studies performed during their neonatal hospitalization stay. In addition, we compared their general characteristics with those not developing IVH. RESULTS: One hundred and sixty asphyxiated newborns met the criteria for hypothermia. Fifteen of these newborns developed IVH, leading to an estimate of 9% (95% CI: 5.3-15.0%) of IVH in this population of newborns. Fifty-three percent had hemorrhage limited to the choroid plexus or IVH without ventricular dilatation; 47% had IVH with ventricular dilatation or parenchymal hemorrhage. Sixty-seven percent had an initial normal brain imaging; the diagnostic brain imaging that demonstrated the IVH was obtained either during cooling (in 30%), within 24 h of the rewarming (in 30%), or 24 h after the rewarming (in 40%). Recurrent seizures were the presenting symptom of IVH during the rewarming in 20% of the newborns. Coagulopathy was more frequent in the asphyxiated newborns developing IVH (p < 0.001). The asphyxiated newborns developing IVH also presented more frequently with persistent pulmonary hypertension, hypotension, thrombocytopenia and coagulopathy (p = 0.03). CONCLUSIONS: The asphyxiated newborns treated with hypothermia appear to be at an increased risk of IVH, especially those with significant hemodynamic instability. IVH seems to develop during late hypothermia and rewarming. Efforts should be directed towards maintaining hemodynamic stability in these patients, even during the rewarming.

Risk factors for intraventricular hemorrhage in term asphyxiated newborns treated with hypothermia.

BACKGROUND: Intraventricular hemorrhage is rare in term newborns. Severe asphyxia is recognized as one of the risk factors of intraventricular hemorrhage in these newborns. Therapeutic hypothermia, which is the only available treatment for the limitation of brain injury in term asphyxiated newborns, may cause fluctuations of cerebral blood flow, possibly placing the newborn more at risk for intraventricular hemorrhage. The literature regarding the incidence of intraventricular hemorrhage in the context of neonatal hypoxic-ischemic encephalopathy and hypothermia is sparse. METHODS: We present a clinical observation and review the literature regarding the risk factors for intraventricular hemorrhage in term asphyxiated newborns treated with hypothermia. RESULTS: We describe the clinical course of a term newborn with severe hypoxic-ischemic encephalopathy who developed significant intraventricular hemorrhage during the rewarming period after the 72-hour hypothermia. CONCLUSION: This newborn presented several risk factors for intraventricular hemorrhage, including severe asphyxia, hemodynamic instability, hemostasis disturbances, instrument delivery, venous sinus thrombosis, and hypoglycemia. Hypothermia and rewarming also may have contributed by causing fluctuations in cerebral blood flow.