Lance H. Rodan

A Citywide Prehospital Protocol Increases Access to Stroke Thrombolysis in Toronto

Background and Purpose— Intravenous tissue plasminogen activator for ischemic stroke is approved for eligible patients who can be treated within a 3-hour window, but treatment rates remain disappointingly low, often <5%. To improve rapid access to stroke thrombolysis in Toronto, Canada, a citywide prehospital acute stroke activation protocol was implemented by the provincial government to transport acute stroke patients directly to one of 3 regional stroke centers, bypassing local hospitals. This comprised a paramedic screening tool, ambulance destination decision rule, and formal memorandum of understanding of system stakeholders. This report describes the initial impact of the activation protocol at our regional stroke center. Methods— We compared consecutive patients with stroke arriving to our stroke center during the first 4 months of this new triage protocol (February 14 to June 14, 2005) versus the same 4-month period in 2004. Results— The protocol resulted in an immediate doubling in the number of patients with acute stroke arriving to our regional stroke center within 2.5 hours of symptom onset. We observed a 4-fold increase in patients who were eligible for and treated with tissue plasminogen activator. The tissue plasminogen activator treatment rate for ischemic stroke patients increased from 9.5% to 23.4% (P=0.01), and one in 2 patients with ischemic stroke arriving within 2.5 hours received thrombolysis during this period (one in 5 of patients with ischemic stroke overall). The median onset-to-needle time for tissue plasminogen activator-treated patients was significantly reduced. Many implementation challenges were identified and addressed. Conclusions— This prehospital triage was immediately successful in improving tissue plasminogen activator access for patients with ischemic stroke, enabling our center to achieve one of the highest tissue plasminogen activator treatment rates in North America and underscoring the need for coordinated systems of acute stroke care. Sustainability of such an initiative will be dependent on interdisciplinary teamwork, ongoing paramedic training, adequate hospital staffing, bed availability, and repatriation agreements with community hospitals.

Stroke recurrence in children with congenital heart disease

Pediatric arterial ischemic stroke (AIS) carries an important morbidity and mortality burden. Congenital heart disease (CHD) is among the most important risk factors for pediatric AIS. Data on stroke recurrence in childhood CHD are lacking, resulting in uncertainty regarding optimal strategies for preventing recurrence.

Seizures during stroke thrombolysis heralding dramatic neurologic recovery

Seizures during thrombolytic therapy for ischemic stroke have not previously been described as a favorable prognostic sign. We report three patients with severe stroke (NIH Stroke Scale [NIHSS] score 15 to 20) who experienced a seizure during tissue plasminogen activator (tPA) infusion. While initially raising alarm about possible hemorrhage, the seizures heralded dramatic recovery (an immediate 15-point NIHSS score improvement after tPA; NIHSS score 0 or 1 at 24 hours). We propose that the seizures during thrombolysis may indicate cortical reperfusion and/or hyperperfusion due to early recanalization of an acutely occluded intracranial artery.

Anti–Glutamic Acid Decarboxylase Antibody Associated Limbic Encephalitis in a Child Expanding the Spectrum of Pediatric Inflammatory Brain Diseases

Anti–glutamic acid decarboxylase directed antibodies are a rare cause of autoimmune limbic encephalitis that is relatively resistant to immunotherapy. Here we report a 15-year-old boy with nonparaneoplastic, anti–glutamic acid decarboxylase limbic encephalitis presenting with subacute headache, memory disturbance, psychiatric symptoms, and seizures. At onset, his memory disturbance manifested as transient global amnesia-like episodes. Clinical remission was achieved with rituximab, intravenous immunoglobulin, and corticosteroids.

Treatment of ADCY5-Associated Dystonia, Chorea, and Hyperkinetic Disorders With Deep Brain Stimulation A Multicenter Case Series

ADCY5 mutations have been reported as a cause of early onset hyperkinetic movements associated with delayed motor milestones, hypotonia, and exacerbation during sleep. The movement disorder may be continuous or episodic, and can vary considerably in severity within families and in individuals. The authors report a case series of 3 patients with ADCY5 mutations treated with deep brain stimulation after unsuccessful medication trials. All had extensive imaging, metabolic, and genetic testing prior to confirmation of their ADCY5 mutation. Two of the patients had the c.1252C>T; p.R418W mutation, while the youngest and most severely affected had a de novo c.2080_2088del; p.K694_M696 mutation. All had variable and incomplete, but positive responses to deep brain stimulation. The authors conclude that deep brain stimulation may provide benefit in ADCY5-related movement disorders. Long-term efficacy remains to be confirmed by longitudinal observation. ADCY5 should be considered in the differential diagnosis of early onset hyperkinetic movement disorders, and may respond to deep brain stimulation.

Expansion of phenotype and genotypic data in CRB2-related syndrome

Sequence variants in CRB2 cause a syndrome with greatly elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein levels, cerebral ventriculomegaly and renal findings similar to Finnish congenital nephrosis. All reported patients have been homozygotes or compound heterozygotes for sequence variants in the Crumbs, Drosophila, Homolog of, 2 (CRB2) genes. Variants affecting CRB2 function have also been identified in four families with steroid resistant nephrotic syndrome, but without any other known systemic findings. We ascertained five, previously unreported individuals with biallelic variants in CRB2 that were predicted to affect function. We compiled the clinical features of reported cases and reviewed available literature for cases with features suggestive of CRB2-related syndrome in order to better understand the phenotypic and genotypic manifestations. Phenotypic analyses showed that ventriculomegaly was a common clinical manifestation (9/11 confirmed cases), in contrast to the original reports, in which patients were ascertained due to renal disease. Two children had minor eye findings and one was diagnosed with a B-cell lymphoma. Further genetic analysis identified one family with two affected siblings who were both heterozygous for a variant in NPHS2 predicted to affect function and separate families with sequence variants in NPHS4 and BBS7 in addition to the CRB2 variants. Our report expands the clinical phenotype of CRB2-related syndrome and establishes ventriculomegaly and hydrocephalus as frequent manifestations. We found additional sequence variants in genes involved in kidney development and ciliopathies in patients with CRB2-related syndrome, suggesting that these variants may modify the phenotype.

Cerebral hyperperfusion and decreased cerebrovascular reactivity correlate with neurologic disease severity in MELAS.

OBJECTIVE To study the mechanisms underlying stroke-like episodes (SLEs) in MELAS syndrome. METHODS We performed a case control study in 3 siblings with MELAS syndrome (m.3243A>G tRNA(Leu(UUR))) with variable % mutant mtDNA in blood (35 to 59%) to evaluate regional cerebral blood flow (CBF) and arterial cerebrovascular reactivity (CVR) compared to age- and sex-matched healthy study controls and a healthy control population. Subjects were studied at 3T MRI using arterial spin labeling (ASL) to measure CBF; CVR was measured as a change in % Blood Oxygen Level Dependent signal (as a surrogate of CBF) to repeated 10 mmHg step increase in arterial partial pressure of CO2 (PaCO2). RESULTS MELAS siblings had decreased CVR (p ≤ 0.002) and increased CBF (p < 0.0026) compared to controls; changes correlated with disease severity and % mutant mtDNA (inversely for CVR: r = -0.82 frontal, r = -0.91 occipital cortex; directly for CBF: r = +0.85 frontal, not for occipital infarct penumbra). Mean CVR was reduced more in frontal (p < 0.001) versus occipital cortex (p = 0.002); mean CBF was increased more in occipital (p = 0.001) than frontal (p = 0.0026) cortices compared to controls. CBF correlated inversely with CVR (r = -0.99 in frontal; not in occipital infarct penumbra) suggesting that increased frontal resting flows are at the expense of flow reserve. INTERPRETATION MELAS disease severity and mutation load were inversely correlated with Interictal CVR and directly correlated with frontal CBF. These metrics offer further insight into the cerebrovascular hemodynamics in MELAS syndrome and may serve as noninvasive prognostic markers to stratify risk for SLEs. CLASSIFICATION OF EVIDENCE Class III.

L-Arginine Affects Aerobic Capacity and Muscle Metabolism in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes) Syndrome

Objective To study the effects of L-arginine (L-Arg) on total body aerobic capacity and muscle metabolism as assessed by 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) in patients with MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes) syndrome. Methods We performed a case control study in 3 MELAS siblings (m.3243A>G tRNAleu(UUR) in MTTL1 gene) with different % blood mutant mtDNA to evaluate total body maximal aerobic capacity (VO2peak) using graded cycle ergometry and muscle metabolism using 31P-MRS. We then ran a clinical trial pilot study in MELAS sibs to assess response of these parameters to single dose and a 6-week steady-state trial of oral L-Arginine. Results At baseline (no L-Arg), MELAS had lower serum Arg (p = 0.001). On 31P-MRS muscle at rest, MELAS subjects had increased phosphocreatine (PCr) (p = 0.05), decreased ATP (p = 0.018), and decreased intracellular Mg2+ (p = 0.0002) when compared to matched controls. With L-arginine therapy, the following trends were noted in MELAS siblings on cycle ergometry: (1) increase in mean % maximum work at anaerobic threshold (AT) (2) increase in % maximum heart rate at AT (3) small increase in VO2peak. On 31P-MRS the following mean trends were noted: (1) A blunted decrease in pH after exercise (less acidosis) (2) increase in Pi/PCr ratio (ADP) suggesting increased work capacity (3) a faster half time of PCr recovery (marker of mitochondrial activity) following 5 minutes of moderate intensity exercise (4) increase in torque. Significance These results suggest an improvement in aerobic capacity and muscle metabolism in MELAS subjects in response to supplementation with L-Arg. Intramyocellular hypomagnesemia is a novel finding that warrants further study. Classification of Evidence Class III evidence that L-arginine improves aerobic capacity and muscle metabolism in MELAS subjects. Trial Registration ClinicalTrials.gov NCT01603446.

A novel neurodevelopmental disorder associated with compound heterozygous variants in the huntingtin gene

We report compound heterozygous variants in HTT, the gene encoding huntingtin, in association with an autosomal recessive neurodevelopmental disorder. Three siblings presented with severe global developmental delay since birth, central hypotonia progressing to spastic quadraparesis, feeding difficulties, dystonia (2/3 sibs), prominent midline stereotypies (2/3), bruxism (1/3), high myopia (2/3), and epilepsy (1/3). Whole exome sequencing identified compound heterozygous variants in HTT that co-segregated in the three affected sibs and were absent in an unaffected sib. There were no additional variants in other genes that could account for the reported phenotype. Molecular analysis of HTT should be considered, not just for Huntington’s disease, but also in children with a Rett-like syndrome who test negative for known Rett and Rett-like syndrome genes.

MR spectroscopy in pediatric Wernicke encephalopathy

The patient is a 7-year-old girl with a history of repaired gastroschisis and short gut syndrome. She presented with a 4-day history of progressive encephalopathy, truncal ataxia, and omnidirectional gaze-evoked nystagmus. Peripheral lactate was 7.1 mmol/L. Serum thiamine level was decreased (<5 nmol/L). Brain magnetic resonance with spectroscopy is shown in the figure. A clinical diagnosis of Wernicke encephalopathy was made. The patient was started on thiamine and demonstrated a rapid clinical recovery. Peripheral lactate normalized within 1 day. Increased lactate has been reported in thiamine deficiency, presumed secondary to the role of thiamine as a cofactor for the pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase.1