GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome

OBJECTIVE: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. METHODS: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. RESULTS: Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. CONCLUSIONS: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia

Rare pediatric movement disorders : clinical aspects of genotype, phenotype, and assessment

Pediatric movement disorders are defined by an impaired ability to initiate and control movements. Dystonia, one of these disorders, may cause a life-long severe motor disability. Pharmacological treatment is often insufficient, but deep brain stimulation (DBS) has turned out to be effective for some dystonia subtypes. Reliable and valid assessment tools are needed to evaluate new interventions for dystonia. The Dyskinesia Impairment Scale (DIS) is an assessment scale for dystonia and choreoathetosis, designed for children and youth with dyskinetic cerebral palsy. However, the DIS is comprehensive, and its administration and scoring times are long, and the scale is often disregarded in a clinical setting. The overall aim of this thesis was to enable and facilitate assessment of dystonia and choreoathetosis in children and young adults, and to elucidate some clinical aspects in two rare pediatric-onset dystonia disorders. Study I: This prospective long-term case series indicates that benign paroxysmal torticollis of infancy does not lead to neurological sequelae. At the last follow-up, with a mean age of 14 years, all 11 children attended regular school, and no one reported motor problems. Five had developed migraine and/or episodic syndromes that may be associated with migraine. We found no known mutations in candidate genes. Nevertheless, in the case of a severe phenotype, specifically if there are paroxysmal disorders in the family history, it may be important to follow the children longitudinally and genetic testing can be considered. Study II: This retrospective multi-center case series confirms that pallidal DBS is an effective treatment option for individuals with DYT-THAP1 dystonia. Fourteen individuals were followed for a median time of nearly five years, and at the last follow-up, median dystonia reduction was about 60% when assessed with the Burke–Fahn–Marsden Movement Scale (BFM-M). However, improvement was less obvious in the orolaryngeal and craniocervical regions; anatomical areas which are often affected by dystonia in these individuals. Study III: This cross-sectional two-center study was an instrument evaluation of the DIS for a new population; children and young adults with inherited or idiopathic dystonia. The DIS and the dystonia subscale were shown to have good-to-excellent inter-rater and test–retest reliability, whereas the choreoathetosis subscale had moderate inter-rater and excellent test–retest reliability. Concurrent validity for the dystonia subscale, when compared with the gold standard BFM-M, was good. Altogether, these results indicate that the DIS might be a valuable tool to evaluate dystonia and choreoathetosis in inherited and idiopathic dystonia. Study IV: This cross-sectional two-center study aimed to design a more clinically useful version of the DIS, the DIS-II. Scale development included an online advisory expert meeting, iterative discussions within the research team, and a Rasch measurement model analysis. With a reduced number of scoring steps, the DIS-II evaluates 60% of the items in the original DIS. The result from the Rasch analysis demonstrates evidence of construct validity of the scale. Furthermore, a high person reliability indicates that the DIS-II may separate assessed individuals into eight distinct ability levels. Altogether, this implies that the DIS-II provides valid and reliable measures for dystonia and choreoathetosis and reduces administration and scoring times in comparison with the DIS

Treatment of Paroxysmal Dyskinesia

Paroxysmal dyskinesia (PxD) is a heterogeneous group of syndromes characterized by recurrent attacks of abnormal movements, triggered by detectable factors, without loss of consciousness. According to the precipitating factors, they are classified as paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dystonia (PED). PxD treatment is based on the combination of nonpharmacologic and pharmacologic approaches. Pharmacologic and nonpharmacologic treatments effective for PNKD and PED also are available. In PxD refractory to conventional treatment, surgery might be an alternative therapeutic option. The course of PRRT2-PKD and MR-1-PNKD is benign, and treatment might not be needed with advancing age

Akutna intoksikacija deltametrinom u mačke – prikaz slučaja

Deltamethrin is a synthetic type II pyrethroid insecticide that is widely used to protect vegetables, fruits and agricultural crops against pests such as mites, ants, beetles and weevils. Moreover, it is used in veterinary practice as an ectoparasiticide, but it is not approved for feline use. To my knowledge, deltamethrin intoxication in cats has never been reported before. For the first time, this report aimed to report clinical, haematological and biochemical changes due to deltamethrin intoxication in a cat. The cat had complaints of involuntary movements and difficulty in standing because the owner sprayed his kittens to treat lice infestation with a watery solution of a pesticide containing deltamethrin, and the mother cat licked its kittens. In the clinical examination of the cat – incoordination, spontaneous contractions, ataxia, hyperesthesia, hypothermia (T: 37.2°C), bradycardia (128/bpm), tachypnea, mydriasis and erosive lesions in the tongue – were detected. Hematologic examination revealed leukocytosis and neutrophilia. Biochemical analysis showed an increase in AST, LDH and CK-MB activities and potassium levels. Given that there is no specific antidote to deltamethrin toxicity, symptomatic treatment was given. Fluid therapy (0.9% NaCl and 5% dextrose solution at a dose of 40 ml/kg, IV) was administered for the elimination of the toxin from the body and coping with septic shock. Diazepam (0.5 mg/kg, IV) was administered to alleviate neurological signs. Enrofloxacin (5 mg/ kg, SC) was administered for three days due to sepsis, leukocytosis and neutrophilia. In the treatment of hypothermia, blankets and hot water bottles were used. After this treatment, the cat recovered. This case report, confirms that deltamethrin, like other pyrethroids, is quite toxic to cats, the clinical findings appeared in a short time, and neurological findings, especially choreoathetosis, were dominant. Consequently, this study demonstrated that deltamethrin causes neutrophilia, leukocytosis, hyperkalaemia, and heart and skeletal muscle damage in cats.Deltametrin je sintetički piretrodni insekticid tipa II koji se široko upotrebljava u zaštiti bilja, voća i poljoprivrednih usjeva protiv štetočina kao što su grinje, mravi, kornjače i korov. U veterinarskoj se praksi upotrebljava kao ektoparaziticid, ali nije odobren za primjenu u mačaka. Prema podacima autora članka intoksikacija deltametrinom u mačaka do sada nije zabilježena i u ovom se članku prvi put bilježe kliničke, hematološke i biokemijske promjene uzrokovane trovanjem deltametrinom u te vrste životinja. U mačke su primijećeni nevoljni pokreti i poteškoće u stajanju nakon što je liznula svoje mačiće koje je vlasnik tretirao vodenastom otopinom pesticida koji je sadržavao deltametrin kako bi ih zaštitio od infestacije ušima. Kliničkim pregledom mačke ustanovljena je inkoordinacija, spontane kontrakcije, ataksija, hiperestezija, hipotermija (37,2 °C), bradikardija (128/otkucaja u minuti), tahipneja, midrijaza i erozivne lezije na jeziku. Hematološki pregled otkrio je leukocitozu i neutrofiliju. Biokemijska analiza pokazala je porast aktivnosti AST-a, LDH-a te CK-MB-a i razine kalija. S obzirom na to da ne postoji specifični antidot toksičnosti deltametrina, primijenjena je simptomatska terapija. Terapija tekućinama (0,9 %-tni NaCl i 5 %-tna otopina glukoze dekstroze u dozi od 40 mL/kg, iv.) primijenjena je kako bi se iz tijela uklonio toksin i spriječio septički šok. Diazepam (0,5 mg/kg, iv.) primijenjen je za ublažavanje neuroloških znakova. Enrofloksacin (5 mg/ kg, sk.) primjenjivan je tri dana zbog sepse, leukocitoze i neutrofilije. U liječenju hipotermije upotrijebljene su deke i termofori. Nakon primjene navedenih terapijskih postupaka mačka se oporavila. Ovaj prikaz slučaja potvrđuje da je deltametrin, kao i drugi piretroidi, prilično toksičan za mačke, da su se klinički znakovi pojavili vrlo brzo i da su dominirali neurološki znakovi, posebno koreoatetoza. Ovo istraživanje također pokazuje da deltametrin uzrokuje neutrofiliju, leukocitozu, hiperkalemiju te oštećenje srca i skeletnih mišića u mačaka

Anticonvulsants-induced chorea: a role for pharmacodynamic drug interaction?

AbstractChorea is a rare side effect of anticonvulsants. We describe three patients who developed chorea secondary to anticonvulsant combination use. A mechanism to explain this finding is proposed.After identification of an index case with anticonvulsant-induced chorea, we reviewed the electronic data base records for all patients with seizures followed in the epilepsy clinics at our university-based hospital for cases of dyskinesia associated with anticonvulsants. Two additional patients , one adult and one pediatric patient were identified.Three patients developed chorea while receiving combination anticonvulsants. Two patients had transient chorea that resolved with withdrawal of one of the drugs. All three patients were using phenytoin and lamotrigine in combination when the chorea started, chorea improved with tapering one of the medications.Polytherapy with certain anticonvulsants may predispose patients to drug-induced chorea. A particular increased risk was seen with combinations that have phenytoin and lamotrigine. This could be due to an additive or a synergistic effect on central dopaminergic pathways