Pediatric Neurotuberculosis: A cases series and review of the literature.

Neurotuberculosis or central nervous system tuberculosis is a form of tuberculous infection that affects any part of the nervous system. Although it is more frequent in adults, pediatric cases have been reported in endemic countries and it is potentially a deadly affection. Therefore, any unusual neurological manifestation in a formerly healthy child, independently of their vaccination status, must bring suspicion of CNS tuberculosis among other diagnoses. We report four cases of pediatric neurotuberculosis with various clinical presentations and outcome and a brief review of the litterature. We conclude that clinical manifestations of pediatric neurotuberculosis are extremely variable and could be misleading. Extra-neurological sites are a key element for diagnosis especially in the pediatric population. A diagnosis and clinical outcome score, especially designed for children might help personalize the therapeutic approach and outcome measures.

Neuronal ceroïd-lipofuscinosis: Clinical, electroencephalographic, imaging, and genetic study of a maghrebian series.

Our study included 13 patients diagnosed with neuronal ceroidlipofuscinosis. It is a group of rare genetically-determined neurodegenerativediseases characterized by clinical and genetic heterogeneity. brain MRI andelectroencephalogram facilitate diagnosis.

Acute Movement Disorders in Childhood: A Cohort Study and Review of the Literature.

OBJECTIVES: Acute movement disorders (AMD) are frequent in neurological and pediatric emergencies. Few studies analyzed AMD in children, none in Tunisia or other African country. The purpose of this study was to describe the peculiarities of AMD in a Tunisian pediatric population with a literature review. METHODS: We conducted a retrospective descriptive study over 8 years including 80 children (sex ratio, 1.05; mean age of onset, 4.8 years) with AMD, followed in tertiary referral Child Neurology Department in North Tunisia. RESULTS: Acute movement disorders were mainly hyperkinetic (n = 67 with dystonia (n = 33; mostly due to inherited metabolic diseases (IMD) in 11; with status epilepticus in 10 children), chorea (n = 14; with Sydenham chorea in 5); myoclonus (n = 14; mostly with opsoclonus-myoclonus syndrome in 10) and tremor (n = 6; of posttraumatic origin in half). Hypokinetic movement disorder (MD) included acute parkinsonism in 5 children of infectious (n = 3), postinfectious (n = 1, malaria) and posttraumatic origin (n = 1). Mixed MD, found in 8 children, were mainly due to IMD in half of them, and to familial lupus in two. Paroxysmal MDs were seen in 2 children, one with multiple sclerosis and one of idiopathic origin. Psychogenic MDs were found in 7 patients mainly of dystonic type. Management of AMD comprised symptomatic treatment according to the phenomenology of the MD and causative treatment depending on its etiology. CONCLUSIONS: Our study illustrated the broad range of AMD in children and the wide spectrum of their etiologies. In our series, we described some exceptional findings and etiologies of AMD in children. These findings may denote a specific profile in of AMD in our country with predominant infectious, postinfectious, and IMD.

Hypomyelination and Congenital Cataract: Clinical, Imaging, and Genetic Findings in Three Tunisian Families and Literature Review.

Hypomyelination and congenital cataract (HCC) is characterized by congenital cataract, progressive neurologic impairment, and diffuse myelin deficiency. This autosomal recessive disorder is caused by homozygous variant in the FAM126A gene. Five consanguineous Tunisian patients, belonging to three unrelated families, underwent routine blood tests, electroneuromyography, and magnetic resonance imaging of the brain. The direct sequencing of FAM126A exons was performed for the patients and their relatives. We summarized the 30 previously published HCC cases. All of our patients were carriers of a previously reported c.414 + 1G > T (IVS5 + 1G > T) variant, but the clinical spectrum was variable. Despite the absence of a phenotype-genotype correlation in HCC disease, screening of this splice site variant should be performed in family members at risk.

Autoimmune Encephalitis in Tunisia: Report of a Pediatric Cohort.

BACKGROUND: Autoimmune encephalitis (AE) is a rapidly progressive encephalopathy caused by antibodies targeting neurons in the central nervous system generating specific immune responses. It is increasingly recognized in children. OBJECTIVE: To describe clinical, neuroimaging, and laboratory features, treatment, and outcome in a cohort of Tunisian children with AE. METHODS: We conducted a retrospective review of the medical records of all children attending the Department of Child and Adolescent Neurology (Tunis) with autoimmune encephalitis between 2004 and 2020. Clinical, neuroimaging, laboratory features, therapeutic data, and outcome were analyzed. RESULTS: Nineteen children were included in the study (12 girls and 7 boys). The median age at diagnosis was 7.68 years (range: 10 months-13 years). The most frequent manifestations were seizures and behavioral disorders. Eleven cases were diagnosed with anti-NMDA receptor encephalitis, 4 cases with anti-Ma2 encephalitis, 3 cases with anti-GAD encephalitis, and 1 case with anti-SOX1 encephalitis. Brain MRI showed increased T2 and fluid-attenuated inversion recovery (FLAIR) signal of the temporal lobe in 5 patients. Eighteen patients showed improvement following first-line immunotherapy (high-dose corticosteroids, intravenous immunoglobulin). One patient with anti-GAD encephalitis died despite escalating immunotherapy. CONCLUSION: Diagnosis of autoimmune encephalitis is challenging in children, because of misleading presentations. An early and accurate diagnosis is important to enable proper therapeutic interventions.

Rasmussen's Encephalitis: A Report of a Tunisian Pediatric Case and Literature Review.

Rasmussen's encephalitis (RE) is a rare progressive inflammatory disease of the central nervous system. It is characterized by unilateral hemispheric atrophy, pharmacoresistant focal seizures, and progressive neurological deficit. The exact etiopathogenesis still remains unknown. Brain imaging plays an important role in diagnosis and follow-up. Fluctuation of lesions in brain imaging was reported in few cases. Herein, we report an additional pediatric case of Rasmussen encephalitis with fluctuating changes in brain MRI.

ABCB1 Polymorphisms and Drug-Resistant Epilepsy in a Tunisian Population.

BACKGROUND: Epilepsy is one of the most common neurological disorders with about 30% treatment failure rate. An interindividual variations in efficacy of antiepileptic drugs (AEDs) make the treatment of epilepsy challenging, which can be attributed to genetic factors such as ATP-Binding Cassette sub-family B, member1 (ABCB1) gene polymorphisms. OBJECTIVE: The main objective of the present study is to evaluate the association of ABCB1 C1236T, G2677T, and C3435T polymorphisms with treatment response among Tunisian epileptic patients. MATERIALS AND METHODS: One hundred epileptic patients, originated from north of Tunisia, were recruited and categorized into 50 drug-resistant and 50 drug-responsive patients treated with antiepileptic drugs (AEDs) as per the International League Against Epilepsy. DNA of patients was extracted and ABCB1 gene polymorphisms studied using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The C1236T, G2677T, and C3435T polymorphisms were involved into AED resistance. Significant genotypic (C1236T TT (p ≤ 0.001); G2677T TT (p = 0.001); C3435T TT (p ≤ 0.001)) and allelic associations (C1236T T (3.650, p ≤ 0.001); G2677TT (1.801, p = 0.044); C3435T T (4.730, p ≤ 0.001)) with drug resistance epilepsy (DRE) were observed. A significant level of linkage disequilibrium (LD) was also noted between ABCB1 polymorphisms. Patients with the haplotypes CT and TT (C1236T-G2677T); GT, TC, and TT (G2677T-C3435T); CT and TT (C1236T-C3435T); CTT, TTC, TGT, and TTT (C1236T-G2677T-C3435T) were also significantly associated to AED resistance. CONCLUSIONS: The response to antiepileptics seems to be modulated by TT genotypes, T alleles, and the predicted haplotypes for the tested SNPs in our population. Genetic analysis is a valuable tool for predicting treatment response and thus will contribute to personalized medicine for Tunisian epileptic patients.

Novel POLR1C mutation in RNA polymerase III-related leukodystrophy with severe myoclonus and dystonia.

INTRODUCTION: RNA polymerase III (Pol III)-related leukodystrophies are a group of autosomal recessive neurodegenerative disorders caused by mutations in POLR3A and POLR3B. Recently a recessive mutation in POLR1C causative of Pol III-related leukodystrophies was identified. METHODS: We report the case of a Tunisian girl of 14 years of age who was referred to our department for evaluation of progressive ataxia that began at the age of 5. Genetic diagnosis was performed by NGS and Sanger analysis. In silico predictions were performed using SIFT, PolyPhen-2, and Mutation Taster. RESULTS: Neurological examination showed cerebellar and tetrapyramidal syndrome, mixed movement disorders with generalized dystonia and severe myoclonus leading to death at 25 years. Brain MRI scans showed diffuse hypomyelination associated with cerebellar atrophy. It also showed bilateral T2 hypointensity of the ventrolateral thalamus, part of the posterior limb of the internal capsule, the substantia nigra and the subthalamic nucleus. Next generation sequencing leukodystrophy panel including POLR3A and POLR3B was negative. Sanger sequencing of the coding regions of POLR1C revealed a novel homozygous mutation. CONCLUSION: The clinical and imaging findings of patients with POLR1C hypomyelinating leukodystrophy are reviewed. Interestingly, severe myoclonic dystonia and T2 hypointensity of the substantia nigra and the subthalamic nucleus are not reported yet and could be helpful for the diagnosis of POLR1C hypomyelinating leukodystrophy.

Muscle-Specific Kinase Autoimmune Myasthenia Gravis: Report of a Pediatric Case and Literature Review.

Myasthenia gravis (MG) with antibodies to the muscle-specific tyrosine kinase (MuSK-MG) receptor is a rare entity. It represents 5 to 8% of all MG patients. Few pediatric cases were reported. Clinical presentation is often atypical. It is characterized by predominant involvement of cranial, bulbar, and axial muscles and early respiratory crises. Myokymia and fasciculation are suggestive of MuSK-MG. The clinical course of patients with MuSK-MG is worse than other types of MG. Responses to standard therapies are variable. We report clinical, neurophysiological, serological, and outcome profile of a Tunisian child with MuSK-MG.

Early Life Epilepsy and Episodic Apnea Revealing an ATP1A3 Mutation: Report of a Pediatric Case and Literature Review.

ATP1A3 mutations have now been recognized in infants, children, and adults presenting with a diverse group of neurological phenotypes, including rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood, and most recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome. The phenotypic spectrum of ATP1A3-related neurological disorders continues to expand. In this case study, we report on early life epilepsy with episodic apnea potentially secondary to ATP1A3 mutation in a Tunisian child.

Pediatric Multiple Sclerosis in Tunisia: A Retrospective Study over 11 Years.

INTRODUCTION: Pediatric multiple sclerosis (pMS) is a rare demyelinating disorder with an onset before the age of 18 years. In this study, we aimed to investigate the characteristics of pMS in Tunisian children. PATIENTS AND METHODS: We conducted a retrospective study over 11 years (2005-2016) including all patients diagnosed with pMS according to the International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria of 2012 and followed up in a tertiary care research center. Epidemiological, clinical, neuroimaging, laboratory, and therapeutic data were collected and analyzed. RESULTS: There were 21 patients. The male-female ratio was 1 : 3. Mean age at onset was 11 years (range: 3-17 years). Three patients had type 1 diabetes. Polyfocal presentation was preponderant (81%) with motor dysfunction in 57% of patients. Paroxysmal dystonia was noticed in 24%. All patients were diagnosed with relapsing-remitting form. Interferon beta was prescribed in 80% with a reduction of annual relapse rate. CONCLUSION: The annual incidence of pMS in Tunisian children aged below 18 years could be estimated as 0.05 per 100,000. Singular features in our cohort were the frequent association with type 1 diabetes and the increased occurrence of dystonia. Greater awareness of pMS may be helpful to improve management strategies of children and their families.

Childhood opsoclonus-myoclonus syndrome: A case series from Tunisia.

INTRODUCTION: Opsoclonus myoclonus syndrome (OMS) is a rare immune-mediated disorder characterized by opsoclonus, myoclonus, ataxia and behavioral changes. The aim of our study was to investigate the epidemiology, clinical features, etiological aspects and outcome of OMS in Tunisian children. METHODS: We conducted a retrospective study over 11years (2005-2016) including all patients aged under 18years who were managed for newly diagnosed OMS in a tertiary care research centre for children with neurological symptoms. Epidemiological and clinical data were analyzed. RESULTS: Fifteen patients were included. The male-female ratio was 7:8. Median age of onset was 4.32years (range: 14months-16years). Time to diagnosis ranged between 2days and 10months. Median follow-up period was 3.8years (range: 2-6years). Acute ataxia was the preponderant inaugural feature. Mean severity score was 9 (range: 3-14). In "Tumor group" (n=7), the main underlying malignancy was neuroblastoma identified in 5 patient. In "No tumor group" (n=8), parainfectious and idiopathic OMS were identified in 5 and 3 patients, respectively. All patients received immunomodulatory treatment. Complete recovery of OMS symptoms was obtained in 12 children. Comparing the "Tumor group" and the "No tumor group", there were no differences in age of onset, sex ratio, main presenting symptom, median OMS severity score or responsiveness to treatment. However, sleep and behavioral disturbances were more frequent in the "No tumor group" (p=0.04). Neurological sequelae were equally found in both groups. CONCLUSION: Annual incidence of OMS in Tunisia could be estimated as 0.6 patients in children per million per year. Diagnosis may be challenging especially when the triad is incomplete. Although behavioral disturbances seem to be more frequent in the "No tumor group", our study suggests that there is no specific features differentiating paraneoplastic OMS from non paraneoplastic OMS. Acute symptoms are responsive to immunomodulatory treatment but long term follow up can reveal neurological (mainly cognitive) sequelae.

Relationship between ABCB1 3435TT genotype and antiepileptic drugs resistance in Epilepsy: updated systematic review and meta-analysis.

BACKGROUND: Antiepileptic drugs (AEDs) are effective medications available for epilepsy. However, many patients do not respond to this treatment and become resistant. Genetic polymorphisms may be involved in the variation of AEDs response. Therefore, we conducted an updated systematic review and a meta-analysis to investigate the contribution of the genetic profile on epilepsy drug resistance. METHODS: We proceeded to the selection of eligible studies related to the associations of polymorphisms with resistance to AEDs therapy in epilepsy, published from January 1980 until November 2016, using Pubmed and Cochrane Library databases. The association analysis was based on pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: From 640 articles, we retained 13 articles to evaluate the relationship between ATP-binding cassette sub-family C member 1 (ABCB1) C3435T polymorphism and AEDs responsiveness in a total of 454 epileptic AEDs-resistant cases and 282 AEDs-responsive cases. We found a significant association with an OR of 1.877, 95% CI 1.213-2.905. Subanalysis by genotype model showed a more significant association between the recessive model of ABCB1 C3435T polymorphism (TT vs. CC) and the risk of AEDs resistance with an OR of 2.375, 95% CI 1.775-3.178 than in the dominant one (CC vs. TT) with an OR of 1.686, 95% CI 0.877-3.242. CONCLUSION: Our results indicate that ABCB1 C3435T polymorphism, especially TT genotype, plays an important role in refractory epilepsy. As genetic screening of this genotype may be useful to predict AEDs response before starting the treatment, further investigations should validate the association.

Anti-Ma2-encephalitis in a 2 year-old child: A newly diagnosed case and literature review.

BACKGROUND: Anti-Ma2-associated encephalitis is a rare paraneoplastic neurological syndrome characterized by isolated or combined limbic, diencephalic, or brainstem dysfunction. It is rarely reported in children. CASE STUDY: We describe the clinical data of a 2-year-old girl referred to our department for refractory focal seizures associated with fever, followed by behavioural changes, speech disturbances and confusional episodes. Brain magnetic resonance imaging (MRI) showed left temporoparietal brain involvement. Haematological, biochemical and infectious evaluations were unremarkable. Autoimmune encephalitis was suspected. Paraneoplastic antibodies tests showed positive results for anti-Ma2 antibodies. Screening for underlying tumour was negative. Immunomodulatory treatment was administrated. The patient showed improvement of vigilance and behaviour. However, she kept refractory epilepsy. CONCLUSION: Although poor response to immunotherapy, early diagnosis and appropriate treatment of this disorder may prevent irreversible sequelae.

Mixed movements disorders as an initial feature of pediatric lupus.

UNLABELLED: Systemic lupus erythematosus (SLE) is an immunologic disease of the early adulthood. In children, SLE is rare and neurological onset is uncommon. We report on an observation of pediatric lupus in heterozygous twins revealed by mixed movement disorders. CASE REPORT: An 8-year-old boy, born to non consanguineous parents, with a family history of depression and a personal history of macular eruption, inflammatory polyarthralgias and a recurrent angina presented with acute movement and mood disorders. Neurological exam showed mild generalized choreic movements with motor and vocal tics. Antinuclear antibodies were positive. Brain MRI was normal. One year after, his twin brother presented with the same features. DISCUSSION: Movement disorders are described in pediatric lupus but are unusual as inaugural features of the disease. In SLE, movement disorders such as chorea are usually reported. However, Tics seem to be exceptional. Pathophysiology remains unclear. Early onset and familial form support genetic implication in the pathogenesis of lupus. CONCLUSION: Immune-mediated movement disorders such as in SLE are an established cause of acute movement disorders in child.

Postencephalitic parkinsonism and selective involvement of substantia nigra in childhood.

Parkinsonism is a rare complication of encephalitis in childhood. Association to an isolated involvement of substantia nigra is exceptional. Mechanisms of nigral cells neurotropism remain hypothetic. We report on three children presenting with postencephalitic parkinsonism and selective involvement of substantia nigra, with literature review and we discuss pathogenic mechanisms.

Status dystonicus in childhood.

BACKGROUND: Status Dystonicus is a rare complication of dystonia. It is a life threatening disorder that needs urgent treatment.The aim of this study is to describe clinical features, management and follow up of children with Status Dystonicus. METHODS: - We conducted a retrospective study over an 8-year period including all patients diagnosed with Status Dystonicus. Clinical characteristics, etiologies and management were analyzed. RESULTS: - Ten patients were included. Main features of Status Dystonicus were a severe generalized dystonia with vegetative signs. Laryngeal spasm and swallowing disorders were observed in 4 cases. Several treatments such as Levodopa, Anticholinergics, Baclofen, Benzodiazepines and Neuroleptics were tried. Mechanical ventilation was required in 4 cases. Two patients died due to rhabdomyolysis and respiratory failure. Others returned to their pre-Status Dystonicus. CONCLUSION: - Status Dystonicus is a life threatening condition that needs an urgent management on an intensive care unit. In fact, patients with Status Dystonicus can develop respiratory failure and metabolic complications.On the basis of our experience, we delineated a therapeutic approach in which the patient with Status Dystonicus needs supportive care, specific therapy of dystonia and intravenous sedative treatment.