L-DOPA AND OCULOGYRIC CRISES

Here we are presenting a case of dengue fever presented with an atypical symptom of “oculogyric crisis” with features of multi organ dysfunction syndrome. Increased vascular permeability, plasma leakage, haemorrhagic manifestations, and thrombocytopenia are charecteristics of dengue fever. A 19 year old male patient, with no co-morbidity came to Dhiraj hospital with chief complaints of fever which was high grade & intermittent, it is associated with chills & rigours for 5 days. Also complain of abdominal pain over epigastric region, dull aching non radiating associated with decreased appetite since 5 days. Dengue infection has a wide range of clinical features. Neurological complications can occur in any spectrum of dengue infection. The diagnosis of oculogyric crisis is majorly clinical and it requires a focused detailed history and detailed physical examination to find out possible triggers for the crisis and to rule out other reasons for abnormal eye movements.

BackgroundArtemether/lumefantrine (AL), sold under the brand name Coartem, is the most common artemisinin-based combination therapy for the treatment of malaria. Drug-induced oculogyric crisis is a neurological disorder characterized by frequent upward deviations of the eye. In the literature, no cases of Coartem-induced oculogyric crisis have been reported in Ghana.Case presentationA 19-year-old male patient, who presented fever measuring 37.9 °C, general body pains, and weakness was prescribed with antimalarial therapy artemether/lumefantrine, Coartem®, from a local pharmacy. Just after initiation of treatment, the patient complained of double vision, involuntary upward eye deviation, and inability to close both eyes. The patient was diagnosed with Coartem-induced oculogyric crisis and was treated with the cessation of the causing agent and intramuscular injection of promethazine hydrochloride.ConclusionsWhen a patient exhibits a neurological disorder, such as oculogyric crisis, with normal conscious state and normal vital signs, special attention should be given to obtaining a history of recently administered medications. Clinicians should recognize adverse reactions to drugs based on a thorough patient history and examination. The goal of this report was to present Coartem-induced oculogyric crisis.

Autoimmune GFAP astrocytopathy presenting with remarkable CNS hyperexcitability and oculogyric crises

Oculogyric crisis is a rare ocular dystonia first appearing at the turn of the last century in postencephalitic patients. In the modern era, they were most frequently associated with first-generation D1 dopaminergic receptor blocking antipsychotic medication.We present an unusual case of acute oculogyric crisis in a 74-year-old woman with long-standing Parkinson disease following exposure to the second-generation neuroleptic ziprasidone, which has dopaminergic (D2) and serotoninergic (5-HT2A) receptor blocking effects and is used for severe delusions and psychosis. To the best of our knowledge, there are no other published reports.

Aromatic l-amino acid decarboxylase deficiency: An extrapyramidal movement disorder with oculogyric crises

The diagnosis of a paroxysmal dyskinesia is difficult and status dystonicus is a rare life threatening movement disorder characterised by severe, frequent or continuous episodes of dystonic spasms. A 25 year old woman with chronic ataxia and paroxysmal dyskinesia presented with facial twitching, writhing of arms, oculogyric crisis and visual and auditory hallucinations. She developed respiratory failure and was ventilated. No cause was found so whole exome sequencing was performed and this revealed a novel, non-synonymous heterozygous variant in exon 11 of the KCNMA1 gene, K457E (c 1369A>G) in the patient but not her parents. This variant has not been previously reported in gnomAD or ClinVar. The finding of a de novo variant in a potassium channel gene guided a trial of the potassium channel antagonist 3,4 diaminopyridine resulting in significant improvement, discharge from the intensive care unit and ultimately home.

Oculogyric crisis induced by risperidone in a child withGRIN1variant

Pearson TS, Gupta N, San Sebastian W, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons. Nat Commun 2021;12(1):4251. doi: 10.1038/s41467-021-24,524-8. Aromatic L-amino acid decarboxylase (AADC) is crucial in catecholaminergic-serotoninergic neurotransmission, which regulates voluntary movement, cognition, emotion, and autonomic processing.1 AADC converts 5-hydroxytryptophan and levodopa (l-DOPA) into serotonin and dopamine, respectively. In turn, dopamine is the precursor of norepinephrine and epinephrine.1 Biallelic variants in the dopa decarboxylase gene (DDC) causes AADC deficiency (AADC-def), a neurometabolic disorder featuring hypotonia, oculogyric crises (OGC), developmental delay, and mood, sleep and autonomic disturbances.1 Brain AADC activity depletion also occurs in Parkinson's disease (PD) following dopaminergic neuron degeneration in substantia nigra pars compacta (SNpc).1, 2 In parallel with AADC-def research, AADC gene therapy has been explored in PD preclinical and phase I/I-II trials for two decades, with the rationale to augment l-DOPA-to-dopamine conversion.2, 3 Direct transfection of striatal/putaminal neurons with an adenoviral vector carrying human DDC (AAV2-hADDC) induces sustained gene expression and dopamine synthesis.2 While exogenous l-DOPA ignites this process in PD, endogenous l-DOPA is intrinsically abundant in AADC-def. Since the first clinical trial, 31 PD and 20 AADC-def patients received intrastriatal/intraputaminal AAV2-hADDC infusion, which is deemed safe and effective.1, 2 Pearson and colleagues4 first investigated AAV2-hADDC delivery to midbrain regions (ie, SNpc and ventral tegmental area) in seven AADC-def cases. Unlike PD, AADC-def is characterized by intact midbrain dopaminergic neurons (including their efferent projections), and anterograde axonal transport to downstream brain structures (eg, striatum) is therefore preserved. The authors postulated that midbrain AAV2-hADDC delivery rescued dopamine synthesis in a wider neural network encompassing nigrostriatal, mesolimbic, and mesocortical pathways, thus ultimately addressing autonomic and affective AADC-def manifestations.4 A novel real-time, MRI-guided, convection-enhanced delivery system (RT-MRI-CED) ensured intraoperative confirmation of catheter placement, continuous monitoring of vector infusion, and enhanced “on-target” infusate distribution. Trial procedure was proven safe and effective in restoring brain AADC activity. Post-operative PET documented appearance of midbrain and striatal 6-[18F]-fluoro-l-DOPA uptake, which was absent at baseline due to defective AADC. Furthermore, after the procedure, CSF homovanillic acid significantly raised, confirming increased dopamine metabolism,4 whereas 5-hydroxyindolacetic and 3-O-methyldopa remained unchanged, which is consistent with exclusion of serotoninergic nuclei and incomplete AADC restoration, respectively.4 The latter suggests that localization rather than magnitude of rescued AADC function may be crucial for clinical improvement.4 Specifically, 6/7 cases achieved OCG remission, 6/7 head control at 12 months, and 6/7 and 2/7 independent sitting and walking at 24 months, respectively. Caregiver diaries documented improvement of behavioral, sleep, and autonomic symptoms. In all cases, irritability, insomnia, and dyskinesia transiently exacerbated within 1 month after surgery, reflecting abrupt increase in dopamine levels.4 By targeting new anatomical regions and optimizing the procedure, Pearson and coworkers4 provides an advanced proof-of-concept disease-modifying strategy to support randomized clinic trials for AADC-def. In keeping with their refined procedure, RT-MRI-CED-guided AAV2-hADDC infusion recently achieved improvement of UPDRS-III “on”-medication score in PD patients, likely due to maximized putaminal infusate coverage compared to previous studies.5 In conclusion, besides therapeutic implications for AADC-def, this study paves the way for designing robust clinical trials investigating AAV2-hADDC as pathomechanism-oriented and possibly long-term treatment for PD, as well as RT-MRI-CED-guided adenoviral vector-mediated gene therapy for other neurometabolic disorders. Francesca Magrinelli would like to thank the Michael J. Fox Foundation and Edmond J. Safra Foundation. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Data Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. M.J.M.: 1B, 1C, 2A, 2B, 3A F.M.: 1B, 1C, 2A, 2B, 3B K.P.B.: 1A, 2C, 3B We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board and patient consent were not required for this work. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. MJM has no disclosures to declare. FM is supported by the Michael J. Fox Foundation and Edmond J. Safra Foundation. KPB has received grant support from Welcome/MRC, NIHR, Parkinson's UK and EU Horizon 2020. He receives royalties from publication of the Oxford Specialist Handbook Parkinson's Disease and Other Movement Disorders (Oxford University Press, 2008), of Marsden's Book of Movement Disorders (Oxford University Press, 2012), and of Case Studies in Movement Disorders–Common and uncommon presentations (Cambridge University Press, 2017). He has received honoraria/personal compensation for participating as consultant/scientific board member from Ipsen, Allergan, Merz and honoraria for speaking at meetings and from Allergan, Ipsen, Merz, Sun Pharma, Teva, UCB Pharmaceuticals and from the American Academy of Neurology and the International Parkinson's Disease and Movement Disorders Society.

Drug-induced dystonic reactions

Tyrosine hydroxylase deficiency is a rare autosomal recessive, treatable disorder of neurotransmission. Fewer than 100 cases have been reported so far. We present a case of a 10‐month‐old infant who was symptomatic since 5 months of age and who received an initial diagnosis of infantile tremor syndrome. She presented with rest tremor, decreased facial expression, global hypokinesia, and later on with oculogyric crisis and dystonia. This diagnosis was revised after confirmation of tyrosine hydroxylase deficiency by CSF neurotransmitter analysis. Genetic studies revealed one previously reported missense variant, p.Thr399Met, and another large deletion starting upstream of exon 1 and encompassing exon 1. She was started on treatment with escalating doses of L‐Dopa/Carbidopa, with folinic acid supplementation. At 3.5 years of age, her cognitive functioning and development is appropriate for age. There is complete subsidence of dystonia and oculogyric episodes. She has occasional chorieform movements which appear to be drug related.

We report a case of oculogyric crisis in a 26-year-old man due to sertindole monotherapy after his first psychotic episode. As far as we know sertindole-induced oculogyric crisis has never been reported.

We report four previously healthy female children, aged between 3 and 8 years, who presented with encephalopathy and an extrapyramidal movement disorder (chorea n=4, rigidity n=2, oculogyric crisis n=2). In addition, an acute behavioural disturbance occurred in two patients and mutism in two others. Seizures heralded the onset of the illness in three patients. Acute MRI was either normal or initially normal with later generalized cerebral atrophy. All infective (including streptococcus), biochemical, and metabolic investigations were normal, although all four patients had oligoclonal bands in the (CSF) but not the serum, indicating intrathecal immunoglobulin synthesis. All four children made an apparently full recovery within four months of the onset. We suggest that these patients represent an immune-mediated movement disorder and encephalopathy syndrome.

Aromatic L-amino acid decarboxylase deficiency is an inborn error of metabolism that leads to combined serotonin and catecholamine deficiency, first described by Hyland et al in 1990. The clinical features, biochemical findings, and treatment of the second family with this condition are reported. Our male patient presented with developmental delay, extreme hypotonia, oculogyric crises, and irritability. The diagnosis of this inborn error of biogenic amine metabolism was accomplished by determining low concentrations of homovanillic, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenyl-ethyleneglycol in cerebrospinal fluid with normal biopterin metabolism and increased L-dopa, in plasma, cerebrospinal fluid, and urine. Greatly reduced activity of aromatic L-amino acid decarboxylase in plasma confirmed this diagnosis. Combined treatment with pyridoxine, tranylcypromine, and bromocriptine produced some clinical improvement.

Sepiapterin reductase deficiency (SRD) is a rare dopa-sensitive neurotransmitter disorder caused by autosomal recessive mutations in the sepiapterin reductase gene. The triad of paroxysmal stiffening, oculogyric crises, and hypotonia are highly suggestive in some patients. However, in other patients, the clinical picture may be nonspecific and remain under-recognized and misdiagnosed as cerebral palsy. We present a nine-month-old boy who initially presented with hypotonia and developmental delay, diagnosed as vitamin B12 deficiency. Upon he did not respond to vitamin replacement treatment, he was diagnosed with SRD by whole-exome sequencing (WES). The boy improved dramatically under treatment with L-dopa, 5-hydroxytryptophan and BH4. We aim to emphasize that SRD can present with nonspecific symptoms, leading to a diagnostic delay for this rare but treatable disease. Moreover, our case is the first to demonstrate the clinical benefit of BH4 add-on treatment. Early intervention is crucial for good outcome and neurodevelopment.

Previously an uninterrupted recovery could confidently have been expected in this type of poisoning once the patient had regained consciousness.This case would suggest that relapse and sudden death may occur in poisoning by tricyclic antidepressant compounds after apparent recovery.The forced diuresis may have kept the patient alive initially and there could be an argument for continuing this treatment in order to wash out the possible second wave of metabolites, which would otherwise contribute to an unexpected relapse.