Case report: Rapid recovery after intrathecal rituximab administration in refractory anti-NMDA receptor encephalitis: report of two cases.

Background: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is one of the most prevalent etiologies of autoimmune encephalitis. Approximately 25% of anti-NMDAR encephalitis cases prove refractory to both first- and second-line treatments, posing a therapeutic dilemma due to the scarcity of evidence-based data for informed decision-making. Intravenous rituximab is commonly administered as a second-line agent; however, the efficacy of its intrathecal administration has rarely been reported. Case summary: We report two cases of severe anti-NMDAR encephalitis refractory to conventional therapies. These patients presented with acute-onset psychosis progressing to a fulminant picture of encephalitis manifesting with seizures, dyskinesia, and dysautonomia refractory to early initiation of first- and second-line therapeutic agents. Both patients received 25 mg of rituximab administered intrathecally, repeated weekly for a total of four doses, with no reported adverse effects. Improvement began 2-3 days after the first intrathecal administration, leading to a dramatic recovery in clinical status and functional performance. At the last follow-up of 6 months, both patients remain in remission without the need for maintenance immunosuppression. Conclusion: Our cases provide evidence supporting the intrathecal administration of rituximab as a therapeutic option for patients with refractory anti-NMDAR encephalitis. Considering the limited penetration of intravenous rituximab into the central nervous system, a plausible argument can be made favoring intrathecal administration as the preferred route or the simultaneous administration of intravenous and intrathecal rituximab. This proposition warrants thorough investigation in subsequent clinical trials.

Altered action potential waveform and shorter axonal initial segment in hiPSC-derived motor neurons with mutations in VRK1.

We recently described new pathogenic variants in VRK1, in patients affected with distal Hereditary Motor Neuropathy associated with upper motor neurons signs. Specifically, we provided evidences that hiPSC-derived Motor Neurons (hiPSC-MN) from these patients display Cajal Bodies (CBs) disassembly and defects in neurite outgrowth and branching. We here focused on the Axonal Initial Segment (AIS) and the related firing properties of hiPSC-MNs from these patients. We found that the patient's Action Potential (AP) was smaller in amplitude, larger in duration, and displayed a more depolarized threshold while the firing patterns were not altered. These alterations were accompanied by a decrease in the AIS length measured in patients' hiPSC-MNs. These data indicate that mutations in VRK1 impact the AP waveform and the AIS organization in MNs and may ultimately lead to the related motor neuron disease.

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort.

BACKGROUND: Clinical and molecular data on the occurrence and frequency of inherited neuromuscular disorders (NMD) in the Lebanese population is scarce. OBJECTIVE: This study aims to provide a retrospective overview of hereditary NMDs based on our clinical consultations in Lebanon. METHODS: Clinical and molecular data of patients referred to a multi-disciplinary consultation for neuromuscular disorders over a 20-year period (1999-2019) was reviewed. RESULTS: A total of 506 patients were diagnosed with 62 different disorders encompassing 10 classes of NMDs. 103 variants in 49 genes were identified. In this cohort, 81.4% of patients were diagnosed with motor neuron diseases and muscular dystrophies, with almost half of these described with spinal muscular atrophy (SMA) (40.3% of patients). We estimate a high SMA incidence of 1 in 7,500 births in Lebanon. Duchenne and Becker muscular dystrophy were the second most frequently diagnosed NMDs (17% of patients). These disorders were associated with the highest number of variants (39) identified in this study. A highly heterogeneous presentation of Limb Girdle Muscular Dystrophy and Charcot-Marie-Tooth disease was notably identified. The least common disorders (5.5% of patients) involved congenital, metabolic, and mitochondrial myopathies, congenital myasthenic syndromes, and myotonic dystrophies. A review of the literature for selected NMDs in Lebanon is provided. CONCLUSIONS: Our study indicates a high prevalence and underreporting of heterogeneous forms of NMDs in Lebanon- a major challenge with many novel NMD treatments in the pipeline. This report calls for a regional NMD patient registry.

Neurobrucellosis: Brief Review.

BACKGROUND: Brucella are small, nonmotile, intracellular, and aerobic gram-negative bacteria. Of the 10 species that currently form the genus Brucella, 5 were shown to be pathogenic in humans. REVIEW SUMMARY: The epidemiology, clinical manifestations, diagnosis and imaging, and treatment of neurobrucellosis will be reviewed.Brucellosis's transmission to humans occurs by direct contact with contaminated animals. Older patients are at increased risk of nervous system involvement in brucellosis. Brucella spp. can lead to central nervous system involvement through direct damage via invasion of neural tissue or indirect damage caused by endotoxins or immune inflammatory reactions elicited by the presence of the bacteria in the body. Patients can have general nonspecific symptoms in addition to neurological and psychiatric symptoms. There are 4 diagnostic criteria for the diagnosis of neurobrucellosis, which include signs and symptoms suggestive of neurobrucellosis, a positive finding of Brucella spp. in the cerebrospinal fluid (CSF), and/or a positive titer of antibodies targeting brucella in the CSF, lymphocytosis with high protein levels and low glucose levels in CSF, and imaging findings (either cranial magnetic resonance imaging or computed tomography) peculiar to neurobrucellosis. For the treatment, a combined therapy is favored over monotherapy for the eradication of Brucella. Moreover, a multirouted therapy has been associated with increased treatment efficacy. The prognosis of neurobrucellosis is dependent on patients' clinical presentation: brucellar meningitis is associated with a good prognosis, whereas diffuse central nervous system involvement is associated with the development of long-term sequelae. CONCLUSIONS: Neurobrucellosis affects patients globally and in endemic areas. Neurologists should familiarize themselves with its clinical presentation, diagnosis, and treatment to provide optimal care for their patients.

Loss of Cajal bodies in motor neurons from patients with novel mutations in VRK1.

Distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of diseases, resembling Charcot-Marie-Tooth syndromes, but characterized by an exclusive involvement of the motor part of the peripheral nervous system. Here, we describe two new compound heterozygous mutations in VRK1, the vaccinia-related kinase 1 gene, in two siblings from a Lebanese family, affected with dHMN associated with upper motor neurons (MNs) signs. The mutations lead to severely reduced levels of VRK1 by impairing its stability, and to a shift of nuclear VRK1 to cytoplasm. Depletion of VRK1 from the nucleus alters the dynamics of coilin, a phosphorylation target of VRK1, by reducing its stability through increased proteasomal degradation. In human-induced pluripotent stem cell-derived MNs from patients, we demonstrate that this drop in VRK1 levels leads to Cajal bodies (CBs) disassembly and to defects in neurite outgrowth and branching. Mutations in VRK1 have been previously reported in several neurological diseases affecting lower or both upper and lower MNs. Here, we describe a new phenotype linked to VRK1 mutations, presenting as a classical slowly progressive motor neuropathy, beginning in the second decade of life, with associated upper MN signs. We provide, for the first time, evidence for a role of VRK1 in regulating CB assembly in MNs. The observed MN defects are consistent with a length dependent axonopathy affecting lower and upper MNs, and we propose that diseases due to mutations in VRK1 should be grouped under a unique entity named `VRK1-related motor neuron disease'.

Neuroleptics as a cause of painful legs and moving toes syndrome.

Painful legs and moving toes syndrome is rare. It is predominantly diagnosed in middle-aged adults following a history of spinal cord surgery or trauma. The syndrome consists of abnormal repetitive movements, most commonly in the lower extremities, accompanied by pain in the affected limb. Pain usually precedes the movements. We report a case in a young patient that we believe was induced by the intake of a low-potency neuroleptic, which was prescribed to him for anxiety. The patient was treated with carbamazepine with mild relief of pain and later on with botulinum injection, which significantly reduced the movements and mildly improved the pain. After stopping the treatment, the beneficial effect lasted for about 3 months after which his condition gradually returned to its initial state.

Neurobrucellosis presenting with hearing loss, gait disturbances and diffuse white matter disease on brain magnetic resonance imaging (MRI).

PURPOSE: To report an unusual case of neurobrucellosis. METHODS: A 48-year-old man was admitted to Rafik Hariri University Hospital (RHUH) for progressive gait disturbances, hearing loss, and some episodes of chills without documented fever. The neurological examination showed gait ataxia, tremor in the legs and mild cognitive decline. The physical exam was otherwise normal. RESULTS: Magnetic resonance imaging (MRI) of brain showed diffuse, bilateral, confluent, subcortical, and periventricular white matter disease. Serum agglutination test (SAT) for Brucella was positive in blood and cerebrospinal fluid (CSF). The patient was treated with a combination of ceftriaxone for one month, and doxycycline and rifampicin for one year and his condition stabilized. Literature review was performed. The possible underlying pathophysiological mechanisms are discussed. CONCLUSION: Neurobrucellosis is a very rare complication of human brucellosis, and can present with a variety of central nervous system symptomatology (CNS) and MRI changes suggestive of leukoencephalopathy. Its diagnosis could be challenging and should always be suspected in patients presenting with CNS manifestations and/or diffuse white matter disease visualized on brain MRI, especially in Brucella endemic areas.

Toxocara canis myelitis: clinical features, magnetic resonance imaging (MRI) findings, and treatment outcome in 17 patients.

Toxocara myelitis is a rare disease. Few cases have been reported in the literature. Patients present with myelopathy, occasional eosinophilia in blood and cerebrospinal fluid (CSF), with abnormal signals on magnetic resonance imaging (MRI). In the current study we report 17 cases of isolated Toxocara myelitis from a single tertiary referral center in Lebanon, with description of the clinical presentation, laboratory data, MRI findings, and response to antihelminthic treatment. Clinical and laboratory data were collected for 17 patients who presented with evidence of spinal cord disease. The clinical presentation included sensory, motor, and autonomic dysfunction, predominantly in the lower extremities. Patients exhibited a subacute or chronic course; this was either slowly progressive or remitting-relapsing with mild to moderate disability. The patients underwent extensive blood and CSF workup as well as MRI of the spinal cord and brain. Only 2 patients had a high eosinophil count in the CSF, although blood eosinophilia was seen in 6 patients. All patients tested positive for Toxocara canis antibodies in the blood and CSF. MRI of the spinal cord revealed a single characteristic lesion in the spinal cord with fusiform enlargement that was isointense on T1-weighted images and hyperintense on T2-weighted images. Nodular enhancement was seen after gadolinium injection. Treatment with albendazole, with or without steroids, resulted in marked neurologic improvement and normalization of the MRI in all patients.The finding of a single inflammatory MRI lesion in the spinal cord with positive Toxocara canis serology in the blood and CSF in cases of subacute or chronic myelitis suggests the diagnosis of Toxocara myelitis, irrespective of the presence of eosinophilia. Antihelminthic treatment is associated with a good outcome.

Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H.

Charcot-Marie-Tooth (CMT) disorders are a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies characterized by muscle weakness and wasting, foot and hand deformities, and electrophysiological changes. The CMT4H subtype is an autosomal recessive demyelinating form of CMT that was recently mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11, in two consanguineous families of Mediterranean origin, by homozygosity mapping. We report here the identification of mutations in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in both families. FRABIN is a GDP/GTP nucleotide exchange factor (GEF), specific to Cdc42, a member of the Rho family of small guanosine triphosphate (GTP)-binding proteins (Rho GTPases). Rho GTPases play a key role in regulating signal-transduction pathways in eukaryotes. In particular, they have a pivotal role in mediating actin cytoskeleton changes during cell migration, morphogenesis, polarization, and division. Consistent with these reported functions, expression of truncated FRABIN mutants in rat primary motoneurons and rat Schwann cells induced significantly fewer microspikes than expression of wild-type FRABIN. To our knowledge, this is the first report of mutations in a Rho GEF protein being involved in CMT.

Moyamoya syndrome with intraventricular hemorrhage in an adult with factor V Leiden mutation.

OBJECTIVE: To report a case of proximal occlusion of 2 major cerebral vessels associated with moyamoya network circulation that manifested by spontaneous intraventricular hemorrhage. DESIGN: Case report. PATIENT AND RESULTS: A 36-year-old Syrian man presented with symptoms of sudden-onset headache, neck stiffness, and confusion. The computed tomography scan of his brain showed intraventricular bleeding, and the subsequent 4 vessel angiographies revealed occlusion of the left middle and anterior cerebral arteries with moyamoya appearance in the terminal branches. The coagulation profile showed the presence of heterozygous factor V Leiden mutation. The patient was treated conservatively until resolution of his blood clot, and later he was started on oral anticoagulation. CONCLUSION: Factor V Leiden mutation may cause large cerebral vessel occlusion with moyamoya syndrome in adults.

Right hemisphere language mapping in patients with bilateral language.

PURPOSE: The configuration of language cortex in the dominant left hemisphere has been well described in the literature. However, language representation in the right hemisphere, particularly in patients with some degree of bilateral language, remains unclear. Herein, we report six patients who underwent electrocortical stimulation (ECS) for language mapping following implantation of a right subdural electrode array (SEA). METHODS: The medical records of six bilateral language patients with right SEA implantation at the Minnesota Epilepsy Group between January 1996 and July 2004 were retrospectively reviewed. Language lateralization was based on the results of the intracarotid amobarbital procedure performed preoperatively. Anatomical localization of the SEA for each patient was verified using colored photographs of the cortical surface before and after SEA placement and by review of MRI scans taken with the SEA in place. Frontal and temporal language areas were identified by errors in any language modality including automatic speech, reading, naming, repetition, and comprehension during ECS. RESULTS: Language maps revealed the presence of frontal and/or temporal language areas analogous to the classic essential language areas of the dominant left hemisphere in four of six patients. One patient had a widespread distribution of single-language-error sites over the right temporal lobe. One patient had a silent language map. CONCLUSION: Our results identified the presence of language cortex in the right hemisphere in five of six patients classified with bilateral language based on intracarotid amobarbital procedure. These areas are assumed to be accessory language zones in relation to the left hemisphere. Further exploratory studies are needed to evaluate their clinical significance.