Role of Nimodipine and Milrinone in Delayed Cerebral Ischemia.

OBJECTIVE: The role of nimodipine and milrinone in the management of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) was studied using clinical and TCD (transcranial Doppler) parameters. METHODS: In this prospective observational study, patients with DCI after aneurysmal SAH presenting between November 2020 and June 2021 who were treated by either intra-arterial nimodipine (IAN) or intravenous milrinone (IVM) were included after excluding patients in whom both IAN and IVM had been given or mechanical angioplasty was performed. Twelve-hourly TCD was performed during the course of the therapy. Clinical improvement and the development of new brain infarcts were also assessed. A P value <0.05 was considered statistically significant. RESULTS: Thirty-four patients fulfilled the inclusion criteria (IVM, 13/34 [38%]; IAN, 21/34 [62%]); patients in the IVM group (vs. IAN group) had poorer median Glasgow Coma Scale score (12 vs. 13), poorer motor response (

"Trapped labelled spins"-related signal on arterial spin labelling in the assessment of flow-diverted aneurysms: preliminary experience.

PURPOSE: To investigate ASL-MRI features of flow-diverted aneurysms, review their haemodynamic surrogates, and discuss their pertinent clinical implications. METHODS: Retrospective single institutional analysis was performed on the clinical and imaging data of patients who underwent digital subtraction angiography (DSA) and ASL-MRI after endovascular flow diversion for cerebral aneurysms. Pseudo-continuous ASL-MRI was performed with post-label delays of 1525-1800 ms. Intra-aneurysmal "trapped labelled spins" (TLS)-related hypersignal, as seen on cerebral blood flow (CBF)-weighted maps of ASL-MRI, was investigated. Intermodality equivalence with DSA [O'Kelly-Marotta (OKM) grading for occlusion], 3D-TOF-MRA, and 3D spin-echo T1-weighted ("black-blood") images was assessed. RESULTS: Ten cases were included. "TLS" signal was demonstrable in 7/8 (87.5%) of the DSA-visible flow-diverted aneurysms (OKM grade B3, n = 6; OKM grade A3, n = 2). No TLS was seen in both OKM-D (excluded) aneurysms. TLS was not visualised in an OKM-B3 aneurysm with < 3 mm opacifying remnant. 3D-TOF-MRA and ASL-MRI were discordant at 5 instances (45.4%; TOF-MRA false negative, n = 4; false positive, n = 1). Loss of flow void on black-blood images corresponded to the absence of TLS and vice versa in all cases but one. CONCLUSION: "Trapped labelled spins"-related signal on ASL-MRI occurs in patent large aneurysms that have undergone successful endovascular flow diversion. This phenomenon likely represents an interplay of a multitude of haemodynamic factors including decelerated intra-aneurysmal inflow and outflow restriction. Serial intra-saccular TLS signal changes may hold diagnostic value, including contexts where 3D-TOF-MRA interpretation becomes dubious. "Trapped labelled spins"-related signal as a non-invasive proxy marker of aneurysm patency can possibly obviate unnecessary DSA.

Intermittent theta burst stimulation of cerebellar vermis enhances fronto-cerebellar resting state functional connectivity in schizophrenia with predominant negative symptoms: A randomized controlled trial.

OBJECTIVE: Negative symptoms of schizophrenia are substantially disabling and treatment resistant. Novel treatments like repetitive transcranial magnetic stimulation (TMS) need to be examined for the same using the experimental medicine approach that incorporates tests of mechanism of action in addition to clinical efficacy in trials. METHODS: Study was a double-blind, parallel, randomized, sham-controlled trial recruiting schizophrenia with at least a moderate severity of negative symptoms. Participants were randomized to real or sham intermittent theta burst stimulation (iTBS) under MRI-guided neuro-navigation, targeting the cerebellar vermis area VII-B, at a stimulus intensity of 100% active motor threshold, two sessions/day for five days (total = 6000 pulses). Assessments were conducted at baseline (T0), day-6 (T1) and week-6 (T2) after initiation of intervention. Main outcomes were, a) Scale for the Assessment of Negative Symptoms (SANS) score (T0, T1, T2), b) fronto-cerebellar resting state functional connectivity (RSFC) (T0, T1). RESULTS: Thirty participants were recruited in each arm. Negative symptoms improved in both arms (p < 0.001) but was not significantly different between the two arms (p = 0.602). RSFC significantly increased between the cerebellar vermis and the right inferior frontal gyrus (pcluster-FWER = 0.033), right pallidum (pcluster-FWER = 0.042) and right frontal pole (pcluster-FWER = 0.047) in the real arm with no change in the sham arm. CONCLUSION: Cerebellar vermal iTBS engaged a target belonging to the class of cerebello-subcortical-cortical networks, implicated in negative symptoms of schizophrenia. However, this did not translate to a superior clinical efficacy. Future trials should employ enhanced midline cerebellar TMS stimulation parameters for longer durations that can potentiate and translate biological changes into clinical effects.

Endovascular management of dissecting posterior cerebral artery aneurysm associated with persistent hypoglossal artery: A case report.

Persistent embryological connections between the anterior and posterior circulations are rare entities. Persistent hypoglossal artery is the second most common persistent carotid-basilar anastomosis. As it is often associated with hypoplasia of vertebral arteries, it poses a challenge during endovascular interventions. We present a case of a 32-year-old woman who presented with occipital headache of four weeks' duration. Magnetic Resonance Angiography showed hypoplastic vertebral arteries with a persistent hypoglossal artery arising from the cervical segment of the left internal carotid artery and supplying the entire posterior circulation, associated with a dissecting aneurysm of the right posterior cerebral artery. Endovascular parent vessel occlusion was performed for the dissecting posterior cerebral artery aneurysm by navigating the guide catheter, microwire, and microcatheter through the persistent hypoglossal artery because the vertebral arteries were hypoplastic. Post-intervention, the patient did not develop any neurological deficit and was discharged in a stable condition.

Conexões embriológicas persistentes entre as circulações anterior e posterior são entidades raras. A artéria hipoglossa persistente é a segunda anastomose carotídeo-basilar persistente mais comum. Como está frequentemente associada à hipoplasia das artérias vertebrais, apresenta um desafio durante as intervenções endovasculares. Apresentamos o caso de uma mulher de 32 anos que apresentou cefaleia occipital com duração de quatro semanas. A angiografia por ressonância magnética mostrou artérias vertebrais hipoplásicas com artéria hipoglossa persistente surgindo do segmento cervical da artéria carótida interna esquerda e suprindo toda a circulação posterior com um aneurisma dissecante da artéria cerebral posterior direita. A oclusão endovascular do vaso parental foi realizada para o aneurisma da dissecção da artéria cerebral posterior pela passagem de cateter guia, microfio e microcateter pela artéria hipoglossa persistente, pois as artérias vertebrais eram hipoplásicas. Após a intervenção, a paciente não apresentou déficit neurológico e recebeu alta em uma condição estável.

Endovascular management of dissecting posterior cerebral artery aneurysm associated with persistent hypoglossal artery: A case report / Tratamento endovascular do aneurisma dissecante da artéria cerebral posterior associado à artéria hipoglossa persistente: relato de caso

Abstract Persistent embryological connections between the anterior and posterior circulations are rare entities. Persistent hypoglossal artery is the second most common persistent carotid-basilar anastomosis. As it is often associated with hypoplasia of vertebral arteries, it poses a challenge during endovascular interventions. We present a case of a 32-year-old woman who presented with occipital headache of four weeks' duration. Magnetic Resonance Angiography showed hypoplastic vertebral arteries with a persistent hypoglossal artery arising from the cervical segment of the left internal carotid artery and supplying the entire posterior circulation, associated with a dissecting aneurysm of the right posterior cerebral artery. Endovascular parent vessel occlusion was performed for the dissecting posterior cerebral artery aneurysm by navigating the guide catheter, microwire, and microcatheter through the persistent hypoglossal artery because the vertebral arteries were hypoplastic. Post-intervention, the patient did not develop any neurological deficit and was discharged in a stable condition.

Resumo Conexões embriológicas persistentes entre as circulações anterior e posterior são entidades raras. A artéria hipoglossa persistente é a segunda anastomose carotídeo-basilar persistente mais comum. Como está frequentemente associada à hipoplasia das artérias vertebrais, apresenta um desafio durante as intervenções endovasculares. Apresentamos o caso de uma mulher de 32 anos que apresentou cefaleia occipital com duração de quatro semanas. A angiografia por ressonância magnética mostrou artérias vertebrais hipoplásicas com artéria hipoglossa persistente surgindo do segmento cervical da artéria carótida interna esquerda e suprindo toda a circulação posterior com um aneurisma dissecante da artéria cerebral posterior direita. A oclusão endovascular do vaso parental foi realizada para o aneurisma da dissecção da artéria cerebral posterior pela passagem de cateter guia, microfio e microcateter pela artéria hipoglossa persistente, pois as artérias vertebrais eram hipoplásicas. Após a intervenção, a paciente não apresentou déficit neurológico e recebeu alta em uma condição estável.

Precipitating hydrophobic injectable liquid embolization of intracranial vascular shunts: initial experience and technical note.

Precipitating hydrophobic injectable liquid is a new liquid embolic agent used mainly for intracranial neurointervention. The agent is ready to use (no shaking is required), since iodine, the radiopaque material, is covalently bonded into the compound. Additionally, due to the absence of tantalum, minimal artifacts are seen on postprocedure follow-up CT scans, and the agent penetrates into vessels smaller than 10 µm. The authors report their initial experience with the use of this agent in neurovascular intervention.

Outcome of epilepsy in patients with mitochondrial disorders: Phenotype genotype and magnetic resonance imaging correlations.

OBJECTIVES: Studies exploring the outcome of epilepsy in patients with mitochondrial disorders are limited. This study examined the outcome of epilepsy in patients with mitochondrial disorders and its relation with the clinical phenotype, genotype and magnetic resonance imaging findings. PATIENTS AND METHODS: The cohort was derived from the database of 67 patients with definite genetic diagnosis of mitochondrial disorders evaluated over a period of 11years (2006-2016). Among this, 27 had epilepsy and were included in final analysis. Data were analyzed with special reference to clinical phenotypes, genotypes, epilepsy characteristics, EEG findings, anti epileptic drugs used, therapeutic response, and magnetic resonance imaging findings. Patients were divided into three groups according to the seizure frequency at the time of last follow up: Group I- Seizure free; Group II- Infrequent seizures; Group III- uncontrolled seizures. For each group the clinical phenotype, genotype, magnetic resonance imaging and duration of epilepsy were compared. RESULTS: The phenotypes & genotypes included Mitochondrial Encephalopathy Lactic Acidosis and Stroke like episodes (MELAS) & m.3243A>G mutation (n = 10), Myoclonic Epilepsy Ragged Red Fiber syndrome (MERRF) & m.8344A>G mutation (n = 4), Chronic Progressive External Ophthalmoplegia plus &POLG1 mutation (CPEO, n = 6), episodic neuroregression due to nuclear mutations (n = 6; NDUFV1 (n = 3), NDUFA1, NDUFS2, MPV17-1 one each), and one patient with infantile basal ganglia stroke syndrome, mineralizing angiopathy &MT-ND5 mutations. Seven patients (25.9%) were seizure free; seven had infrequent seizures (25.9%), while thirteen (48.1%) had frequent uncontrolled seizures. Majority of the subjects in seizure free group had episodic neuroregression & leukoencephalopathy due to nuclear mutations (85.7%). Patients in group II with infrequent seizures had CPEO, POLG1 mutation and a normal MRI (71%) while 62% of the subjects in group III had MELAS, m.3243A>G mutation and stroke like lesions on MRI. CONCLUSIONS: A fair correlation exists between the outcome of epilepsy, clinical phenotypes, genotypes and magnetic resonance imaging findings in patients with mitochondrial disorders. The recognition of these patterns is important clinically because of the therapeutic and prognostic implications.

Novel magnetic resonance imaging findings in a patient with short chain acyl CoA dehydrogenase deficiency.

Reports on magnetic resonance imaging findings in patients with short chain acyl -Coenzyme A dehydrogenase (SCAD) deficiency, an autosomal recessive disorder caused by mutations in the acyl-Coenzyme A dehydrogenase (ACADS), are limited. Many asymptomatic carriers of ACAD variants have also been described necessitating careful evaluation of clinical and biochemical findings for an accurate diagnosis. Here we report a an infant with short chain acyl -Coenzyme A dehydrogenase (SCAD) deficiency diagnosed based on the characteristic biochemical findings and confirmed by genetic testing. He presented with refractory seizures and neuro regression at 4 months of age. His metabolic work up revealed elevated butyryl carnitine in plasma and ethyl malonic acid in urine. Magnetic resonance imaging of the brain showed cortical and basal ganglia signal changes with cortical swelling. Serial scans showed progression of the lesions resulting in cystic leukomalacia with brain atrophy. Exome sequencing revealed a novel homozygous nonsense variation, c.1146C > G (p.Y382Ter) in exon ten of ACADS which was further validated by Sanger sequencing. Both parents were heterozygous carriers. Follow up at 15 months showed gross psychomotor retardation and refractory seizures despite being on optimal doses of anti-epileptic medications, carnitine and multivitamin supplementation. This report expands the phenotypic and genotypic spectrum of SCAD deficiency.

Mitochondrial oxidative phosphorylation disorders in children: Phenotypic, genotypic and biochemical correlations in 85 patients from South India.

Mitochondrial oxidative phosphorylation (OXPHOS) disorders account for a variety of neuromuscular disorders in children. In this study mitochondrial respiratory chain enzymes were assayed in muscle tissue in a large cohort of children with varied neuromuscular presentations from June 2011 to December 2013. The biochemical enzyme deficiencies were correlated with the phenotypes, magnetic resonance imaging, histopathology and genetic findings to reach a final diagnosis. There were 85 children (mean age: 6.9±4.7years, M:F:2:1) with respiratory chain enzyme deficiency which included: isolated complex I (n=50, 60%), multiple complexes (n=24, 27%), complex IV (n=8, 9%) and complex III deficiencies (n=3, 4%). The most common neurological findings were ataxia (59%), hypotonia (59%) and involuntary movements (49%). A known mitochondrial syndrome was diagnosed in 27 (29%) and non-syndromic presentations in 57 (71%). Genetic analysis included complete sequencing of mitochondrial genome, SURF1, POLG1&2. It revealed variations in mitochondrial DNA (n=8), SURF1 (n=5), and POLG1 (n=3). This study, the first of its kind from India, highlights the wide range of clinical and imaging phenotypes and genetic heterogeneity in children with mitochondrial oxidative phosphorylation disorders.

Hypersomnolence-hyperkinetic movement disorder in a child with compound heterozygous mutation in 4-aminobutyrate aminotransferase (ABAT) gene.

Deficiency of gamma-amino-butyrate aminotransferase (ABAT) is a rare inherited disorder. A six-month-old girl presented with hyper-somnolence, hyperkinetic movements of distal extremities during wakefulness, hypotonia, bi-pyramidal signs, and impaired response to sound and visual stimuli. Brain MRI at five months showed restricted diffusion along the internal capsule and genu of corpus callosum. A follow up MRI at 18months, showed hyperintensities in brainstem, external and internal capsule, 'trilaminated' appearance of posterior limb of internal capsule and dysmyelination of sub-cortical white matter. MRS showed a peak between 2.2ppm and 2.4ppm, corresponding to glutamine, glutamate and GABA. EEG was normal at six months but showed multifocal epileptiform discharges at 18months. Targeted exome sequencing revealed compound heterozygous missense variations in ABAT resulting in its reduced function. We report the novel association of hypersomnolence and hyperkinetic movement disorder with ABAT variations thus expanding the clinical spectrum of this uncommon neuro-metabolic disorder and discuss the emerging role of GABA in pathways regulating sleep-wake cycle and movement disorders.

Huppke-Brendel syndrome in a seven months old boy with a novel 2-bp deletion in SLC33A1.

Huppke -Brendel syndrome is a new addition to the evolving spectrum of copper metabolism defects. It is an autosomal recessive disorder characterized by congenital cataract, impaired hearing, and developmental delay with low copper and ceruloplasmin. It is caused by defects in SLC33A1 that codes for acetyl CoA transporter protein. Reports on variation in this gene causing human disease is extremely scarce and the metabolic link between this gene and copper metabolism is yet to be identified. Here we report a seven months old infant with Huppke-Brendel Syndrome. In addition to the already reported features, he also had hypo pigmented hair and hypogonadism. His magnetic resonance imaging revealed hypo myelination and cerebellar hypoplasia. Clinical exome sequencing revealed a homozygous two base pair deletion, c.542_543delTG (p.Val181GlyfsTer6) in exon 1 of the SLC33A1. This report expands the phenotypic and genotypic spectrum of Huppke Brendel syndrome.

Peripheral neuropathy in genetically characterized patients with mitochondrial disorders: A study from south India.

BACKGROUND: There are relatively few studies, which focus on peripheral neuropathy in large cohorts of genetically characterized patients with mitochondrial disorders. This study sought to analyze the pattern of peripheral neuropathy in a cohort of patients with mitochondrial disorders. METHODS: The study subjects were derived from a cohort of 52 patients with a genetic diagnosis of mitochondrial disorders seen over a period of 8 years (2006-2013). All patients underwent nerve conduction studies and those patients with abnormalities suggestive of peripheral neuropathy were included in the study. Their phenotypic features, genotype, pattern of peripheral neuropathy and nerve conduction abnormalities were analyzed retrospectively. RESULTS: The study cohort included 18 patients (age range: 18 months-50 years, M:F- 1.2:1).The genotype included mitochondrial DNA point mutations (n=11), SURF1 mutations (n=4) and POLG1(n=3). Axonal neuropathy was noted in 12 patients (sensori-motor:n=4; sensory:n=4; motor:n=4) and demyelinating neuropathy in 6. Phenotype-genotype correlations revealed predominant axonal neuropathy in mtDNA point mutations and demyelinating neuropathy in SURF1. Patients with POLG related disorders had both sensory ataxic neuropathy and axonal neuropathy. CONCLUSION: A careful analysis of the family history, clinical presentation, biochemical, histochemical and structural analysis may help to bring out the mitochondrial etiology in patients with peripheral neuropathy and may facilitate targeted gene testing. Presence of demyelinating neuropathy in Leigh's syndrome may suggest underlying SURF1 mutations. Sensory ataxic neuropathy with other mitochondrial signatures should raise the possibility of POLG related disorder.