To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS.
Methods:
Multicenter retrospective study.
Results:
A total of 144 children and adolescents (median age 8 years, range 0.7–17; 103 female) with NMDA receptor (NMDAR) encephalitis (n = 39), opsoclonus myoclonus ataxia syndrome (n = 32), neuromyelitis optica spectrum disorders (n = 20), neuropsychiatric systemic lupus erythematosus (n = 18), and other neuroinflammatory disorders (n = 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05–9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range 0.1–8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0–2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0–2 was greater in patients given rituximab early in their disease course compared to those treated later.
Conclusion:
While limited by the retrospective nature of this analysis, our data support an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality.
Classification of evidence:
This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections.
Abstract Objective To investigate intrathecal inflammation using cerebrospinal fluid (CSF) cytokines and chemokines in a subgroup of pediatric epilepsy patients with frequent daily seizures. Methods We measured 32 cytokines/chemokines using multiplex immunoassay in CSF collected from pediatric patients with febrile infection‐related epilepsy syndrome (FIRES)/FIRES‐related disorders (FRD; n = 6), febrile status epilepticus (FSE; n = 8), afebrile status epilepticus (ASE; n = 8), and chronic epilepsy with frequent daily seizures (n = 21) and compared the results with noninflammatory neurological disorders (NIND; n = 20) and encephalitis (n = 43). We also performed longitudinal CSF cytokine/chemokine studies in three cases with FIRES/FRD. Results The median age of onset of seizures was 2.4 years (range = 0.08‐12.5). Median CSF timing from the onset of seizures was longer in chronic epilepsy (540 days), whereas FIRES, FSE, and ASE had CSF tested within 1‐2 days of onset of seizures ( P < .001). The elevation of cytokines/chemokines was higher in FIRES followed by FSE, when compared to chronic epilepsy and NIND controls. Th1‐associated cytokines/chemokines (TNF‐α, CXCL9, CXCL10, CXCL11), IL‐6, CCL2, CCL19, and CXCL1 ( P < .05) were elevated in FIRES, in contrast to the elevation of a broader network of cytokines/chemokines in encephalitis. The cytokines/chemokines (CXCL9, CXCL10, CXCL11, and CCL19) were elevated in FSE when compared to ASE despite the similar median seizure duration and timing of CSF testing in relation to seizures. Chronic epilepsy generally lacked significant elevation of cytokines/chemokines despite frequent daily seizures. The median concentrations of the cytokines/chemokines rapidly declined on serial testing during the course of illness in all three FIRES/FRD cases. Significance We identify significant differences in CSF cytokine/chemokine profile between FIRES/FRD and encephalitis. The prominent elevation of CSF cytokines and chemokines in FIRES/FRD and to a lesser extent FSE highlights that the cytokine/chemokine elevation is significantly associated with the etiology of the underlying process rather than purely reactive. However, it is unclear whether the immune activation contributes to the disease process.
AFG3L2 mutations are associated with several neurodegenerative disorders.1-5 The ATP-dependent mitochondrial AAA+ metalloprotease (m-AAA) has 2 subunits: AFG3L2 and paraplegin. AFG3L2 is encoded by the gene AFG3L2 and paraplegin is encoded by the gene, SPG7.6 AFG3L2 subunits form homo-oligomeric complexes or hetero-oligomeric complexes with paraplegin, located in the mitochondrial inner membrane, essential for protein quality control.6 We report the first family with AFG3L2-related autosomal dominant optic atrophy (DOA) and intellectual disability with two members having the additional manifestation of dopamine responsive dystonia parkinsonism. The proband is a 13-year-old boy with optic atrophy and moderate intellectual disability diagnosed at 5-years of age. At 7.5-years of age, he presented with progressive limb dystonia, where symptoms worsened towards the end of the day when he would require assistance for mobilizing. He walked at an appropriate age, though always with in-toeing and intermittent toe-walking. At 7.5 years of age, examination showed dystonic lower limb posturing at rest, a dystonic gait with foot inversion, toe walking, arm flexion, and loss of arm swing, and parkinsonian features of paucity of facial expression, bradykinesia, shuffling when turning and postural instability (Video 1, segment 1). Segment 1 demonstrates the dystonia and mild parkinsonism of III-3 at 7.5-years-old. There is gait dystonia, bradykinesia, shuffling when turning and asymmetric dystonic posturing of his upper limbs. Segment 2 shows III-3 on 4 mg/kg/day of levodopa. There is significant improvement in the gait but with some subtle arm posturing and left foot inversion still present whilst running with his unaffected sibling, Segment 3 shows III-3 at 13-years-old with more prominent parkinsonism. He has a bradykinetic, stooped gait. Segment 4 shows subtle gait dystonia with bilateral feet inversion and reduced right arm swing and subtle posturing in III-4 prior to levodopa. Video content can be viewed at https://onlinelibrary.wiley.com/doi/10.1002/mdc3.13538 MRI head showed isolated hypoplastic optic nerves. Cerebrospinal fluid analysis revealed low biopterin 14.96 nmol/L (25.00–45.00), homovanillic acid 0.259 μmol/L (0.345–0.716) and HVA:5-HIAA ratio 1.46 (2.30–4.00) with normal protein, glucose, lactate, and amino acids. These findings were consistent with a potential diagnosis of GTP cyclohydrolase deficiency, which was not supported by genetic analysis as outlined below. Serum alpha-fetoprotein, copper, caeruloplasmin, uric acid and thyroid function testing and urine metabolic screen were normal. Chromosome microarray was normal. Next generation sequencing in 2016 using a 130-gene movement disorder panel (TruSight One panel [FC-141-1007] on an Illumina NextSeq550) did not identify any pathogenic or likely pathogenic variants, including full coverage of all known disorders of monoamine metabolism. Levodopa trial at 4 mg/kg/day resulted in significant, but incomplete improvement in dystonia (Video 1, segment 2) enabling maintenance of independent ambulation throughout the day. However, his dystonia gradually worsened with escalating levodopa requirements. At recent review at 13-year-old on levodopa 12.5 mg/kg/day, the patient had more prominent parkinsonism with a stooped posture and difficulty initiating movements (Video 1, segment 3). Whole genome sequencing conducted as part of Economic and Psychosocial Impacts of Caring for Families Affected by Intellectual Disability study, ethics reference no: HREC/16/HNE/309, identified a heterozygous pathogenic missense variant in AFG3L2 (NM_006796.2:c.1064C>T; p.(Thr355Met)), previously reported in a family with DOA and hyperkinetic movements, ataxia and dystonia.1 The variant was absent from the gnomAD database and classified as pathogenic (ACMG with modifications; PP1_strong, PM2, PS4_supporting, PM1_supporting, PP3).7 Several family members had optic atrophy and variable intellectual disability (Fig. 1): proband (III-3), mother (II-2), three brothers (III-2, III-4, III-6), maternal cousin (III-8) and maternal uncle (II-4). Dystonia emerged in III-4 at 11-years of age (Video 1, segment 4), partially responsive to 3 mg/kg/day levodopa. III-7 had mild limb dystonia when running at 5-years of age but no optic atrophy or intellectual disability and remains under review. II-2 and II-4 had sensorineural hearing loss and ataxia with ophthalmoplegia only seen in II-4. The AFG3L2 variant segregated to affected family members and was absent in II-1, III-1, III-5 and III-9 (Fig. 1). Clinical details of individuals with the AFG3L2 variant are shown in Table 1 and Video 2. Sensorineural hearing loss Dysarthric speech (cerebellar) Gait ataxia (cerebellar) Sensorineural hearing loss Complex ophthalmoplegia Spastic ataxia Right ankle deformity Dopa responsive dystonia Parkinsonism Full video from the 2021 Video Challenge discussion of this case. Video content can be viewed at https://onlinelibrary.wiley.com/doi/10.1002/mdc3.13538 Previously, heterozygous variants in AFG3L2 were described in DOA and autosomal dominant spinocerebellar atrophy type 28 (SCA28), while homozygous or compound heterozygous variants were described in distinct neurodegenerative disorders, including spastic ataxia type 5 (SPAX5).1-5 SCA28 manifests as adult-onset, slowly progressive cerebellar ataxia and SPAX5 has a severe phenotype of early-onset spasticity, cerebellar ataxia, oculomotor apraxia and progressive myoclonic epilepsy with basal ganglia and cerebellar abnormalities on brain MRI.2, 5 DOA associated with AFG3L2 variants was described in 12 families, with some individuals exhibiting additional phenotypic features of intellectual disability, sensorineural deafness, spasticity, cerebellar signs, dystonia, myoclonus or chorea.1 This included an individual with the same mutation as this report (p.T355M) and an overlapping phenotype but no details on levodopa response. AFG3L2 interacts with OPA1, which encodes a mitochondrial GTPase responsible for the fusion of the inner mitochondrial membrane, and disease-causing variants in OPA1 are responsible for 75% of cases of autosomal dominant DOA.8 Many monogenic disorders of dopamine biosynthesis, such as GTP cyclohydrolase 1 deficiency remain stable in severity and levodopa response, while levodopa responsiveness can also be noted in otherwise progressive disorders, like some cases of ataxia telangiectasia and neuronal intranuclear inclusion disease.9 Progressive dystonia has been reported in AFG3L2-related disorders, but levodopa responsive dystonia had not been previously reported. However, a 25-year-old female with heterozygous variants in both AFG3L2 and SPG7 (AFG3L2:p.R468C and SPG7:p.Glu127SerfsTer2) was described with progressive manifestations of optic atrophy, cognitive impairment, spastic ataxia and levodopa responsive parkinsonism.10 The AFG3L2 variant in this individual had been reported in DOA with mild intellectual disability suggesting concurrent AFG3L2 and paraplegin defects likely cause a distinct defect resulting in a complex, neurodegenerative phenotype. Our proband did not have variants in SPG7 or OPA1. It has not been explicitly described how dysfunction of the AFG3L2 subunit results in altered neurotransmitter levels in the central nervous system and dopamine responsiveness of the subsequent movement disorder. We postulate that this effect may be mediated through two possible pathways. The first possible mechanism is by the dysregulation of Ca2+ homeostasis, as mitochondria play a crucial role in modulation of neuronal cell Ca2+ levels, which can result in altered neurotransmitter release.11 Secondly, Magri et al10 demonstrated abnormal dopaminergic uptake in the basal ganglia on single photon emission computed tomography (SPECT)/dopamine transporter (DaT) scan in their proband with concurrent AFG3L2 and SPG7 variants. Additionally, Baderna et al8 showed in functional studies that a variant in AFG3L2 close to the AAA domain of the protein (as in our family) resulted in destabilization of the long isoforms of OPA1 leading to mitochondrial fragmentation. Finally, variants in the OPA1 gene have been causative for genetic forms of Parkinson's disease with functional studies showing the mitochondrial dysfunction associated with this results in a significant loss of dopaminergic synapses.12 Whilst this is still postulation, the relationship between some AFG3L2 variants and OPA1 dysfunction may be a factor in the dopamine responsive nature demonstrated in our family. To our knowledge, our index case is the first described patient with AFG3L2-related, progressive levodopa responsive dystonia parkinsonism in a family with AFG3L2-related DOA, intellectual disability, and additional neurological manifestations. We propose that in addition to optic atrophy, dystonia, with or without parkinsonism, may be a prominent manifestation of AFG3L2-related disease and a trial of levodopa therapy is warranted. We wish to thank the family for allowing us to share their story. We would like to thank Dr Michael Buckley for his assistance with the genetic analysis. We would like to thank Dr Deborah Schofield for her role in the family's diagnosis as part of the Economic and Psychosocial Impacts of Caring for Families Affected by Intellectual Disability study. Open access publishing facilitated by The University of Sydney, as part of the Wiley - The University of Sydney agreement via the Council of Australian University Librarians. WW: 1A, 1B, 1C, 2A, 2B. CT: 1A, 1C, 2B. RCD: 1A, 2B. TR: 1C, 2B. MF: 1C, 2B. EP: 1C, 2B. EMM: 1C, 2B. KRK: 1B, 1C, 2B. SSM: 1A, 1B, 1C, 2B. The use of diagnostic and clinical information of patients in this study complied with the requirements of the clinical ethics committee of the Children's Hospital at Westmead. Verbal and written informed consent for use of information and videos was gained from the patients (when adult consent was possible) or the parents of the patients for those under the age of 14 years of age. All authors 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. No specific funding was received for this work and the authors declare that there are no conflicts of interest relevant to this work. SSM was supported by the Cerebral Palsy Alliance, Australia (award number PG01217). KRK receives salary from NSW Health, funding from the Paul Ainsworth Family Foundation, the Michael J. Fox Foundation Aligning Science Across Parkinson's (ASAP) initiative, and honorarium from Abbvie, Seqirus and Research Review Australia. Table S1 Characteristics of individuals reported with AFG3L2 variants with manifestations of dystonia or parkinsonism Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder of the nervous system that classically presents with a combination of characteristic eye movement disorder and myoclonus, in addition to ataxia, irritability, and sleep disturbance. There is good evidence that OMAS is an immune-mediated condition that may be paraneoplastic in the context of neuroblastoma. This syndrome may be associated with long-term cognitive impairment, yet it remains unclear how this is influenced by disease course and treatment. Treatment is largely predicated on immune suppression, but there is limited evidence to indicate an optimal regimen.
Methods
Following an international multiprofessional workshop in 2004, a body of clinicians and scientists comprising the International OMS Study group continued to meet biennially in a joint professionals and family workshop focusing on pediatric OMAS. Seventeen years after publication of the first report, a writing group was convened to provide a clinical update on the definitions and clinical presentation of OMAS, biomarkers and the role of investigations in a child presenting with OMAS, treatment and management strategies including identification and support of long-term sequelae.
Results
The clinical criteria for diagnosis were reviewed, with a proposed approach to laboratory and radiologic investigation of a child presenting with possible OMAS. The evidence for an upfront vs escalating treatment regimen was reviewed, and a treatment algorithm proposed to recognize both these approaches. Importantly, recommendations on monitoring of immunotherapy response and longer-term follow-up based on an expert consensus are provided.
Discussion
OMAS is a rare neurologic condition that can be associated with poor cognitive outcomes. This report proposes an approach to investigation and treatment of children presenting with OMAS, based on expert international opinion recognizing the limited data available.
and 11 oz. in weight; not congested.Liver enlarged, con- gested, and fatty, weighing 3 lb.and 41/2 oz., or about normal; small pieces floated on the surface of water.Kidneys both congested ; the right weighed 5 oz., and the left 5 oz.The stomach, bowels, and the head were not examined.Remarks.—With regard to the pericarditis it may be ob- served that the man during the past ten years was never under treatment for rheumatism, nor did he during his fatal illness complain of symptoms of pericarditis, which in this case was no doubt of a chronic nature.The next point of pathological interest is the cause of death by syncope, and which was revealed at the autopsy-namely, a very fatty condition of the heart.The pneumonia, I believe, was set up, and which, although caused by the fatty heart, in its turn embarrassed that organ in its feeble action.It may also be remarked that in this case salicin had little or no effect in reducing the temperature.Agar, India.
'/%3e%3c/defs%3e%3cpath fill='%23012169' d='M0 0h10080v5040H0z'/%3e%3cpath stroke='%23fff' stroke-width='.6' d='m0 0 6 3m0-3L0 3' clip-path='url(%23b)' transform='scale(840)'/%3e%3cpath stroke='%23e4002b' stroke-width='.4' d='m0 0 6 3m0-3L0 3' clip-path='url(%23c)' transform='scale(840)'/%3e%3cpath stroke='%23fff' stroke-width='840' d='M2520 0v2520M0 1260h5040'/%3e%3cpath stroke='%23e4002b' stroke-width='504' d='M2520 0v2520M0 1260h5040'/%3e%3cg fill='%23fff'%3e%3cuse xlink:href='%23d' x='2520' y='3780'/%3e%3cuse xlink:href='%23a' x='7560' y='4200'/%3e%3cuse xlink:href='%23a' x='6300' y='2205'/%3e%3cuse xlink:href='%23a' x='7560' y='840'/%3e%3cuse xlink:href='%23a' x='8680' y='1869'/%3e%3cuse xlink:href='%23e' x='8064' y='2730'/%3e%3c/g%3e%3c/svg%3e)
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
