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Background Brown-Vialetto-Van Laere syndrome-2 (BVVLS2) is a rare autosomal recessive neurological disorder caused by mutations in the SLC52A2 gene, which is characterized by early childhood onset of sensorineural hearing loss, bulbar palsy, peripheral neuropathy, and respiratory insufficiency. We aimed to investigate the genetic cause of a 4-year-old boy who suffered from BVVLS2 whose initial presentation was severe normocytic anemia and had been overlooked for three years in a local hospital. He was misdiagnosed with pure red cell aplasia (PRCA) and treated with hormones and chemotherapy drugs, but there was no obvious effect. Methods The targeted capture of 927 genes associated with neuromuscular disorders and next-generation sequencing were performed. Sanger sequencing was employed to verify the variant mutations. Results The proband was found to be heterozygous for c.350T > C (p.L117P) in exon 3 and c.1135_1137delTGG (p.W379del) in exon 5 of SLC52A2 gene. His anemia and neurological symptoms improved significantly after treatment with low dose oral riboflavin. Conclusions This study expands the mutational spectrum of SLC52A2 and phenotypic spectrum of BVVLS2, which provides a foundation for further investigations elucidating the SLC52A2 related mechanisms of BVVLS2. A low-dosage of riboflavin supplementation was used to obtain good curative effect, which provides further future references for the clinical treatments of BVVLS.

Background Osmotic demyelination syndrome commonly occurs after rapid correction of hyponatremia. But it has also been reported after graded correction of hyponatremia in the presence of other risk factors like chronic alcoholism, malnutrition, liver disease, and hypokalemia. Case Report We report a case of a 67-year-old man who presented with dysphagia and nasal regurgitation and had features suggestive of bulbar palsy on neurological examination. He had spontaneous rapid correction of hyponatremia from a serum sodium level of 122 mEq/L to 132 mEq/L after discharge from our hospital. Neuroimaging was suggestive of extrapontine myelinolysis involving the basal ganglia. Why Should an Emergency Physician Be Aware of This? An emergency physician should be aware of this because osmotic demyelination syndrome should also be considered in the differential diagnosis of patients presenting with bulbar palsy to the emergency department.

Background Compared with typical bulbar onset amyotrophic lateral sclerosis (ALS), isolated bulbar palsy (IBP), an often under-understood variant of ALS, is characterized by symptoms confined to bulbar region for extended periods and relative preservation of limb and ventilation function. To find a cutoff value of disease duration that can distinguish IBP from typical bulbar onset ALS well, the association of survival with disease progression in bulbar onset ALS patients was analyzed. Methods Clinical data of bulbar onset ALS patients were collected from January 2009 to December 2013. The duration from bulbar onset to first significant limb involvement was analyzed by a cutoff point analysis with maximally selected log-rank statistics and dichotomized to categorize patient outcomes. The patients were divided into two groups, the IBP and typical bulbar onset ALS groups, according to the cutoff value. Clinical features were compared. Results 115 bulbar onset ALS patients were recruited, and the duration from bulbar onset to first significant limb involvement was associated with survival (P P = 0.047; P = 0.004; P = 0.031). The median survival time of the IBP group was significantly longer than that of the typical bulbar onset ALS group (64 months and 26 months, respectively; P Conclusions A cutoff duration of 20 months from bulbar onset to first significant limb involvement may be used to specifically distinguish IBP from typical bulbar onset ALS. IBP was characterized by female predominance, relative preservation of limb function, more pure UMN bulbar signs and a relatively benign prognosis.

Background: Children comprise only 1–5% of COVID-19 cases. Recent studies have shown that COVID-19 associated multisystem inflammatory syndrome in children (MIS-C) can present with neurological signs and symptoms. In this systematic review and meta-analysis, we have reviewed neurological involvement in these patients. Methods: A comprehensive electronic literature search was done on PubMed, Google Scholar, Embase, Cochrane database, and SCOPUS for the published English language articles from December 1, 2019, to February 28, 2021. A meta-analysis of the proportion was expressed as a pooled proportion with a 95% confidence interval (CI). Representative forest plots showing individual studies and the combined effect size were generated to provide an overview of the results.Results: This systematic review and meta-analysis analyzed 15 published MIS-C studies with a total of 785 patients. Neurological manifestations in patients with MIS-C was found in 27.1%. We found that 27% developed headaches, 17.1% developed meningism/meningitis and 7.6 % developed encephalopathy. Other uncommon neurological manifestations of MIS-C includes anosmia, seizures, cerebellar ataxia, global proximal muscle weakness and bulbar palsy. In MIS-C patients with neurological feature, neuroimaging showed signal changes in the splenium of the corpus callosum. Electroencephalography showed slow wave pattern and nerve conduction studies and electromyography showed mild myopathic and neuropathic changes. Conclusions: Our study revealed that neurological manifestations are not uncommon in patients with MIS-C. Further large prospective studies are needed to better explore the disease spectrum and to unravel the underlying pathophysiology.Keywords: Children; COVID-19; kawasaki disease; MIS-C, neurology

Amyloidosis, a disease with extracellular tissue deposition of fibrils, results in clinical manifestations based on deposition of these fibrils in multiple organ systems. Usual manifestations include nephrotic‐range proteinuria, cardiac failure, hepatosplenomegaly, and skin manifestations. Common neurological manifestations include peripheral and autonomic neuropathies. Cranial neuropathy has been seldom reported and is an unusual clinical feature of amyloidosis. Here, we report an older man who presented with cranial nerve palsies along with other clinical features, including heart failure, proteinuria, weight loss, anorexia and distal symmetric polyneuropathy and was diagnosed with immunoglobulin light‐chain (AL) amyloidosis.

A pediatric case with Bickerstaff’s brainstem encephalitis (BBE), which is a very rare monophasic post-infectious condition characterized by central nervous system involvement, unconsciousness, ophthalmoplegia and ataxia, is presented. Twelve years old patient was brought with difficulty in eye movements and ataxia. On the second day, she became agitated and lethargic, and then bulbar palsy and whole body paralysis developed. Upper motor neuron involvement was evident. Routine biochemical parameters and serologic tests, cranial magnetic resonance imaging, lumbar puncture, autoimmune, paraneoplastic, and electrophysiological studies were evaluated. All were normal except for the encephalopathic first electroencephalography (EEG) and the EEG repeated on the 25th day was reported to be normal. Anti-ganglioside antibody, anti-GQ1b was found positive. Intravenous immunoglobulin (IVIG) started on the fourth day. A very rapid improvement was seen in the first week of IVIG treatment. She was able to walk in the second week. She was completely normal in 3 months. Although seven years passed, our patient has not had any relapse or neurological deficit. We presented a case diagnosed as BBE treated successfully with single dose intravenous Immunoglobulin. We wanted to emphasize that BBE has a good prognosis even though it is an acutely developing severe condition.

Objective: To describe the clinical-laboratory profile of pediatric Guillain-Barre syndrome and delineate features associated with need of mechanical ventilation. Methods: In a prospective observational study at tertiary care hospital, clinical-laboratory assessment and nerve conduction studies were documented in consecutive children hospitalized with Guillain-Barre syndrome according to Brighton criteria. Clinical-laboratory features were compared between ventilated and nonventilated patients using univariate and multivariate analysis. Results: Forty-six children (27 boys) with a mean age of 69.1±35.2 months were enrolled. History of preceding infection was present in 47.8%, bulbar palsy in 43.5%, feeble voice in 41.3%, sensory involvement in 13%, and autonomic involvement in 39.5%. Tetraparesis was noted in 87% of cases. Hughes disability scale >3 was noted in 44 children at admission and 39 (84.7%) at discharge. The most common electrophysiological type was acute motor axonal neuropathy (46.5%) followed by acute motor sensory axonal neuropathy (39.5%), acute inflammatory demyelinating polyneuropathy (7%), and inexcitable nerves (7%). Nine (19.7%) children were ventilated, 3 (6.5%) died or were lost, and 43 were discharged. Factors associated with need of mechanical ventilation on univariate analysis were older age, hypertension, bulbar palsy, feeble voice, lower Medical Research Council (MRC) sum, raised total leucocyte count, and history of preceding infection. Logistic regression revealed older age, history of predisposing illness, lower MRC sum at presentation, and bulbar palsy as independent predictors of mechanical ventilation. Conclusions: The most common electrophysiological subtype in northern Indian children is acute motor axonal neuropathy. Older age, preceding infection, low MRC sum, and bulbar palsy are predictors of mechanical ventilation in pediatric Guillain-Barre syndrome.

OBJECTIVE To investigate changes in serum complements and their regulators in the pathogenesis of myasthenia gravis (MG). METHODS Forty-four patients with acetylcholine receptor antibody-positive MG, as well as 20 patients with non-inflammatory neurological disorders were enrolled. Serum complements (C3, C4 and soluble C5b-9) and complement regulators (vitronectin, clusterin and properdin) were extensively analysed by enzyme-linked immunosorbent assay and their associations with clinical profiles of MG were examined. RESULTS Serum C3, C4 and clusterin levels were not significantly different between patients with MG and controls. The patients with MG had higher soluble C5b-9 (P = 0.09) and vitronectin (P = 0.001) levels than the controls; moreover, vitronectin levels decreased after treatment (P = 0.09). Serum properdin (P = 0.03) levels were lower in the patients with MG than in the controls, and negatively correlated with the MG Activities of Daily Living score (rs = -0.26, P = 0.09) and with the presence of bulbar palsy (P = 0.04). CONCLUSION Our results show that activation of complements and an altered complement network could contribute to the inflammatory pathogenesis of MG.

Alternating hemiplegia of childhood (AHC) (MIM 104290) is characterized by transient repeated attacks of paresis on either or both sides of the body, oculomotor and autonomic abnormalities, movement disorders, and cognitive impairment. Preventing paroxysmal attacks, such as paresis and spasm, in patients with AHC is often difficult. An 8-month-old girl presented to our institution with intractable epilepsy. She developed AHC, with left-right alternating or bilateral recurrent plegia upon waking, involuntary movements, eye movement abnormalities, and psychomotor retardation. She had a heterozygous de novo p.E815K mutation in the ATP1A3gene. Patients with this mutation develop severe hemiplegic spells and convulsions, have a poor neuromotor developmental outcome, and are particularly difficult to treat. Flunarizine treatment has limited therapeutic effect in such patients; however, it was definitely effective for bulbar palsy in the present case. The present case further highlights the need for the development of other new treatments, such as a ketogenic diet.

Patients with infantile Alexander disease (AxD) usually do not survive beyond their early teens without life support care because of progressive central hypoventilation. We present the autopsy report of a woman with infantile AxD carrying an R239C mutation in the glial fibrillary acidic protein gene, who survived 39 years. She presented with psychomotor retardation in infancy and regressed after age 5. Brain computed tomography scans showed bilateral low frontal white matter density. She became quadriplegic with bulbar palsy and was intellectually handicapped after a measles infection at age 7. Tube feeding was introduced because of dysphagia at age 15. Noninvasive positive pressure ventilation was required due to central hypoventilation in her early thirties. She died of neurogenic respiratory failure at 39 years. Autopsy findings revealed a markedly atrophic brain (709 g, −6.0 standard deviation), especially in the frontal lobe, cerebellum, and brainstem portions. We found demyelination, gliosis, and cystic lesions throughout the brain, and we saw Rosenthal fibers accumulating in the perivascular spaces. We also identified a variety of abnormalities in other organs such as pancreatic necrosis, completely desquamated epithelium in the lower esophagus and stomach, foreign-body giant cells in the colon submucosa, glomerular sclerosis, and multiple bladder stones. This is the first autopsied case report of a patient with infantile AxD with long survival, who showed not only central nervous system characteristic findings, but also unexpected pathological changes in other organs.

Objectives: Isolated bulbar palsy (IBP) is a rare variant that can show a benign course, while progressive bulbar palsy (PBP) has been regarded as a bulbar-dominant type of classical amyotr...

The Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare neurological disorder that may present at all ages with sensorineural hearing loss, bulbar palsy and respiratory compromise. We describe a 6-year-old male patient who suffered bilateral sudden onset severe hearing loss for two years. Audiological investigations revealed sudden onset auditory neuropathy spectrum disorder bilaterally. He also had neurological complaints. During riboflavin therapy an improvement in hearing loss and the benefit of hearing aids were observed. In BVVLS, it is difficult to plan and apply auditory rehabilitation interventions and the results vary from patient to patient. In audiological evaluation, it should be borne in mind that subjective and objective tests are complemental. Early medical intervention and regular audiological follow-up are very important for effective hearing rehabilitation in the patients with BVVLS.

Guillain-Barré syndrome (GBS) has an annual incidence rate ranging from 0.4 to 1.7 cases per 1,00,000 population. Pharyngeal-cervical-brachial (PCB) variant is an extremely rare variant of GBS (3%), which presents with muscle weakness initially involving the neck, oropharynx, and upper extremities. GBS often has an infectious inciting event leading to an autoimmune response. There has been an increase in the incidence of GBS during the COVID-19 pandemic, and several case studies have shown an association between the development of GBS and COVID-19 infection. High clinical suspicion is needed to reach a diagnosis. As PCB variant of GBS can have fatal outcomes, a good clinical knowledge of its presentation can allow timely life-saving interventions. Here, we report a case of GBS with acute onset of neck and respiratory muscle weakness that progressed to upper limb weakness. The patient developed these symptoms two weeks after the onset of cough, fever, and malaise. PCB variant of GBS should always be considered as an important differential diagnosis in any patient presenting with limb weakness and bulbar palsy.

We treated a patient with mesenteric lymphoma who concomitantly developed amyotrophic lateral sclerosis (ALS). The patient died of urinary tract infection nine months after the onset of ALS. We herein report the changes in the patient's condition and the sequence of events until death from the viewpoint of a physiotherapist. The patient was a 69-year-old woman who developed mesenteric lymphoma in September of X year and perceived weakness in the toes in November of X year. She showed signs of upper and lower motor neuron disorders, and electrophysiologic testing revealed denervation in three areas of the spinal cord. In March of X+1 year, she was diagnosed with definite ALS based on the Awaji criteria. In April of X+1 year, she began to receive continuous home healthcare, specifically outpatient rehabilitation. No remarkable bulbar palsy was observed soon after the initiation of rehabilitation; however, manual muscle testing revealed strengths in the lower and upper limbs of 1 and 3-5, respectively, indicating muscle weakness and muscle atrophy. She developed exacerbation of neurological symptoms in the upper limbs, bulbar palsy, and respiratory muscle paralysis during rehabilitation. The ALS Functional Rating Scale-Revised indicated a decreased tendency to X [please define X]. In July of X+1 year, the mesenteric lymphoma had enlarged, resulting in the development of ureteric obstruction and ultimately causing hydronephrosis. Urinary tract infection and sepsis were diagnosed, and she was hospitalized. Although her fever temporarily subsided following ceftriaxone administration, she ultimately died due to a systemic inflammatory response syndrome three days after hospitalization. The mean period between the ALS onset and death is reportedly 40.6±33.1 months. The rate of ALS progression differs among individuals. Malignant tumors and paraneoplastic neurological syndrome may be involved in rapidly worsening neurological symptoms. Patients who concomitantly develop motor neuron disorders and malignant tumors are likely to have a higher risk of developing serious conditions associated with the exacerbation of neurological symptoms and complications. Our patient had several diseases that affected her survival prognosis; however, the sharing of information regarding her condition among healthcare professionals may have been insufficient. The primary physician responsible for treating each disease should cooperate with physiotherapists and other paramedical staff who have frequent opportunities to talk to patients in daily clinical practice. In geriatric patients in particular, such an environment is essential.

Background: Spinal and bulbar muscular atrophy (SBMA) is an X-lined motor neuron disease characterized by progressive muscle weakness, bulbar palsy, and dysphagia. Dysphagia is associated with tongue weakness, which is a common manifestation of SBMA. This study aimed to investigate the correlations between tongue pressure and dysphagia in patients with SBMA.Materials and Methods: Thirty-nine genetically confirmed SBMA patients underwent a videofluoroscopic swallowing study (VFSS) and tongue pressure assessment. Then, we analyzed the maximal tongue pressure (MTP), oral transit time, penetration-aspiration scale (PAS), videofluoroscopic dysphagia scale (VDS), amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and 6-min walk test (6MWT). Pearson and Spearman correlation coefficients were calculated to analyze the association of the MTP with clinical, swallowing, and functional parameters.Results: In the correlation analysis, MTP was negatively correlated with disease duration (r = −0.396, p = 0.013) and VDS (r = −0.426, p = 0.007), and positively correlated with ALSFRS-R (r = 0.483, p = 0.002) and 6MWT (r = 0.396, p = 0.013). The bulbar (r = 0.367, p = 0.022) and gross motor (r = 0.486, p = 0.002) domains of the ALSFRS-R were correlated with MTP.Conclusion: Tongue pressure assessment can be used as a safe and easy tool to assess swallowing function in SBMA patients. Moreover, MTP reflects functional states, including activities of daily living and gait performance, showing it to be a potential biomarker for physical performance in SBMA.

Oropharyngeal dysphagia can cause chronic aspiration leading to significant respiratory symptoms. When dysphagia is diagnosed, an underlying cause is sought. We present a case series of 15 children diagnosed aged 6 months to 5 years (mean 2y 5mo; 11 males, four females) over a 6-year period, who were found to have an isolated bulbar palsy on genioglossus electromyography, with no accompanying neurological or neurodevelopmental disorder. Eight children had dysphagia but a normal EMG. In those with isolated bulbar palsy, management included thickened fluids (n=13), cooled boiled water (n=1), and nasogastric tube feeding (n=1). Follow-up over 1 to 8 years (mean 5y) showed complete resolution in six children, improvement in four children, and no improvement in five children (including two requiring fluids via a gastrostomy). Eight children no longer had any respiratory symptoms. Isolated bulbar palsy is under-recognized and has not been reported previously as a cause of significant dysphagia in children.

Objectives Adult onset Alexander Disease (AxD) is a rare leukodystrophy for which there is currently no treatment. Ceftriaxone has been proposed as a potential treatment for AxD. Here we report the clinical outcome of an extended course of intravenous cyclical ceftriaxone therapy in two patients with AxD. Methods Case 1 is a 64 year old female with a five year history of progressive gait disturbance, bulbar palsy and horizontal diplopia. Case 2 is an 80 year old male with a two-year history of bulbar palsy and gait disturbance. Both cases were confirmed to have AxD and received intravenous ceftriaxone 2g daily for three weeks per month during the initial four months, then for 15 days monthly thereafter. Patients were assessed at baseline and approximately 4-month intervals using the Kurtzke Expanded Disability Status Scale, Modified Ranking Scale, and neurological examination. Results Both cases displayed functional decline on ceftriaxone therapy, as assessed by outcome measures of disability. Progression on neuroimaging was also observed on MRI brain for both patients. Conclusions These results suggest that ceftriaxone for AxD may not prevent functional decline. Caution should be applied before suggesting ceftriaxone for the management of AxD.

Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric acidemia type II, is classically caused by a congenital defect in electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH). Flavin adenine dinucleotide synthase (FADS) deficiency caused by mutations in FLAD1 was recently reported as a novel riboflavin metabolism disorder resembling MADD. Here, we describe a Japanese boy with FADS deficiency due to a novel mutation (p.R249*) in FLAD1. In the asymptomatic male infant born at full term, newborn screening showed positive results with elevated C5 and C14:1 acylcarnitine levels and an increased C14:1/C2 ratio. Biochemical studies were unremarkable except for lactic acidosis (pH 7.197, lactate 61 mg/dL). A diagnosis of MADD was suspected because of mild abnormalities of the acylcarnitine profile and apparent abnormalities of urinary organic acids, although mutations in the ETFA, ETFB, ETFDH, and riboflavin transporter genes (SLC52A1, SLC52A2, and SLC52A3) were not detected. Administration of riboflavin and L-carnitine was initiated at one month of age based on the diagnosis of “biochemical MADD” despite a lack of symptoms. Nevertheless, the acylcarnitine profile was not normalized. Symptoms resembling bulbar palsy, such as vocal cord paralysis and dyspnea with stridor, were present from 3 months of age. At 4 months of age, he became bedridden because of hypoxic-ischemic encephalopathy due to fulminant respiratory failure with aspiration pneumonia. At 2 years and 5 months of age, a homozygous c.745C > T (p.R249*) mutation in the FLAD1 gene was identified, confirming the diagnosis of FADS deficiency. His severe clinical course may be caused by this nonsense mutation associated with poor responsiveness to riboflavin. Persistent lactic acidosis and neuropathy, such as bulbar palsy, may be important for diagnosing FADS deficiency. Although the biochemical findings in FADS deficiency are similar to those in MADD, their clinical symptoms and severity may not be identical.

We report the neuropathology of a patient with a family history of amyotrophic lateral sclerosis (ALS) and a p.N345K mutation in the transactivation response DNA-binding protein 43 kDa (TDP-43) gene (TARDBP). A 62-year-old man had bulbar palsy with progressive weakness in the extremities. Neurological examination revealed evident upper motor neuron signs and lower motor neuron involvement corroborated by needle electromyography. The patient was diagnosed as having probable ALS according to the revised El Escorial diagnostic criteria and was eventually diagnosed with familial ALS. At 65 years of age, respiratory failure became critical, and artificial ventilation was initiated. At 70 years of age, the patient died from a urinary tract infection. Histopathological investigation showed Bunina bodies in the remaining motor neurons and anterolateral funicular myelin pallor in the spinal cord. TDP-43-positive cytoplasmic inclusions were quite rare in the spinal cord motor neurons, being predominantly present in the glial cells (especially astrocytes) of the spinal cord anterior horn. Although the reason for the preferential vulnerability of spinal glial cells to TARDBP mutations remains unclear, our findings indicate that TARDBP p.N345K mutation could have an influence on the topography of TDP-43 aggregation.

A 53-year-old man suffering from squamous cell lung cancer presented with bilateral ptosis and bulbar palsy a month after initial treatment with the immune checkpoint inhibitor nivolumab. The symptoms showed worsening from midday, suggesting myasthenia gravis (MG), although anti-AChR antibody was negative. Although no muscle weakness was detected, the CK level was elevated to 5,255 IU/l, and MRI of the thigh revealed inflammation of the bilateral rectus femoris muscle. A muscle biopsy showed signs of necrotizing myopathy with expression of sarcolemmal HLA class I and accumulation of macrophages, CD4, CD8, and CD20-positive lymphocytes. Positivity for anti-titin antibody, one of the anti-striated muscle antibodies, was evident. The patient was diagnosed as having nivolumab-related necrotizing myopathy with myasthenia gravis, an immune-related adverse event (irAE). Treatment with prednisolone rapidly ameliorated the symptoms, and the serum CK level normalized. There have been several reports of nivolumab-related myositis with MG. On the basis of the muscle pathology and antibody data, we were able to clarify that necrotizing myopathy was related to the pathogenesis of this case.

Introduction: Mitochondrial diseases are characterized by considerable clinical and genetic heterogeneity. Mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS) and Leigh syndrome (LS) are both established mitochondrial syndromes; sometimes they can overlap.Methods: A retrospective observational cohort study was done to analyze the clinical manifestations, biochemical findings, neuroimaging and genetic data, and disease outcomes of 14 patients with identified MELAS/LS overlap syndrome.Results: A total of 14 patients, 9 males and 5 females, were enrolled. The median age at onset was 14 years, while the average age was 12.6 years. As for clinical features in concordance with MELAS, the top three most common symptoms were seizures, cognitive impairment, and stroke-like episodes (SLE). Brain atrophy was present in seven patients. As for the clinical hallmarks of LS, the top three most common symptoms were ataxia, spastic paraplegia, and bulbar palsy. Patients presented with individual syndrome or overlap syndromes with similar frequency, and the prognosis did not seem to be related to the initial presentation. Thirteen patients were identified with MTND mutations, among which m.13513G>A mutation in the MT-ND5 gene was the most common. Only one patient with m.8344A>G mutation of MTTK gene was found.Discussion: Our study demonstrated that MTND genes are important mutation hot spots in MELAS/LS overlap syndrome. The follow-up is very important for the final diagnosis of overlap syndrome.

Objective: To delineate the comprehensive clinical features of anti-GQ1b antibody syndrome in childhood.Methods: The clinical data of children diagnosed with anti-GQ1b antibody syndrome at two Chinese tertiary pediatric neurology centers were collected and analyzed. We also conducted a systematic literature review on anti-GQ1b antibody syndrome in children.Results: This study included 78 children with anti-GQ1b antibody syndrome, consisting of 12 previously unreported cases from the two Chinese centers. The median onset age was 10 years (range, 2–18 years). The most common phenotype was acute ophthalmoparesis (32%), followed by classic Miller Fisher syndrome (15%), and Bickerstaff brainstem encephalitis (12%). External ophthalmoplegia (48%), sensory disturbance (9%), and bulbar palsy (9%) were the three most frequent onset symptom manifestations. Brain or spinal lesions on MRI and abnormal recordings by nerve conduction study were present in 18% (12/68) and 60% (27/45) of cases, respectively. There was CSF albuminocytologic dissociation in 34% of the patients (23/68). IV immunoglobulin alone or combined with steroids or plasma exchange was administered to 58% of patients (42/72). We did not find a significant correlation between early improvement up to 3 months and age onset and phenotype. All patients showed different degrees of recovery, and 81% (57/70) had complete recovery within 1 year.Conclusions: Acute ophthalmoparesis and classic Miller Fisher syndrome are the most common phenotypes of anti-GQ1b antibody syndrome in childhood. The majority of patients show good response to immunotherapy and have favorable prognosis.

Purpose/Objective(s) Brainstem toxicity after radiation is a devastating complication and a particular concern with proton radiation (RT), given the biological differences and range uncertainties at the distal edge of proton beam. Data from St. Jude's found a 3.7% risk of brainstem necrosis after photon-based RT, while the incidence with protons ranges from 0.7% - 31% across studies. We investigated the incidence and clinical correlates of brainstem injury in pediatric brain tumors treated with proton therapy. Materials/Methods All patients 30 Gy and/or Dmax > 50.4 Gy were included. We excluded patients with primary brainstem tumors. Symptomatic brainstem injury (SBI) was defined as any new or progressive cranial neuropathy, ataxia, dysmetria and/or motor weakness with corresponding radiographic abnormality within the brainstem and was graded per the NCI Common Terminology Criteria for Adverse Events v5.0 (Grade 2: moderate symptoms, corticosteroids indicated; Grade 3: severe symptoms, medical intervention indicated; Grade 4: life-threatening; urgent intervention; and Grade 5: death). Results A total of 595 patients were reviewed and 362 (medulloblastoma = 209, ependymoma = 86, ATRT = 43, pineoblastoma = 9, others = 15) met our inclusion criteria. Median age at RT was 5 years (range 0.7 – 17.9 years) and median prescribed RT dose was 54 CGyE (range 39.6 – 59.4 CGyE). Median follow up was 40 months (range 1 – 152). Ten patients (2.7%) developed SBI, at a median of 4 months after RT (range 1-6). Grades 2,3,4 and 5 brainstem injuries were seen in 3, 4, 2 and 1 patient respectively. Mean brainstem Dmax in SBI and non-SBI patients was 55.9 Gy and 54.8 Gy (P = 0.30), while the mean Dmean was 43.3 Gy and 43.2 Gy (P = 0.48) respectively. Most common symptoms of SBI were ataxia, slurred speech, 6th cranial nerve palsy and bulbar palsy. All SBI patients required steroids for 1-5 months, while grade 3-5 injuries were also treated with bevacizumab and/or hyperbaric oxygen therapy. Asymptomatic imaging changes within brainstem were seen in 47 patients (13%) at a median of 4 months after RT, most common findings being increased T2 flair, focal enhancement and encephalomalacia. In 2014, our institution started using strict brainstem dose constraints (Dmax ≤ 57 Gy, Dmean ≤ 52.4 Gy and V54 ≤ 10%). The incidence of SBI has decreased from 4.2% (2007-2013) to 0.7% (2014-2019) (P = 0.047) while asymptomatic imaging changes remain similar (11.6% vs 15.1%, P = 0.33). Patients with SBI had a higher V45, V50-52 and D15 -D50; while the Dmax, Dmean, V53-60 and D1- D10 were similar. Conclusion Our results suggest that there is a low risk of SBI after proton therapy for pediatric brain tumors. A lower incidence of SBI was seen after the use of strict brainstem dose constraints. Volumetric doses to brainstem may play a significant role in determining the risk of SBI and developing a dose response nomogram is warranted.

Riboflavin is classified as one of the water-soluble B vitamins. It is part of the functional group of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) cofactors and is required for numerous flavoprotein-catalysed reactions. Riboflavin has important antioxidant properties, essential for correct cell functioning. It is required for the conversion of oxidised glutathione to the reduced form and for the mitochondrial respiratory chain as complexes I and II contain flavoprotein reductases and electron transferring flavoproteins. Riboflavin deficiency has been demonstrated to impair the oxidative state of the body, especially in relation to lipid peroxidation status, in both animal and human studies. In the nervous system, riboflavin is essential for the synthesis of myelin and its deficiency can determine the disruption of myelin lamellae. The inherited condition of restricted riboflavin absorption and utilisation, reported in about 10-15% of world population, warrants further investigation in relation to its association with the main neurodegenerative diseases. Several successful trials testing riboflavin for migraine prevention were performed, and this drug is currently classified as a Level B medication for migraine according to the American Academy of Neurology evidence-based rating, with evidence supporting its efficacy. Brown-Vialetto-Van Laere syndrome and Fazio-Londe diseases are now renamed as "riboflavin transporter deficiency" because these are autosomal recessive diseases caused by mutations of SLC52A2 and SLC52A3 genes that encode riboflavin transporters. High doses of riboflavin represent the mainstay of the therapy of these diseases and high doses of riboflavin should be rapidly started as soon as the diagnosis is suspected and continued lifelong. Remarkably, some mitochondrial diseases respond to supplementation with riboflavin. These include multiple acyl-CoA-dehydrogenase deficiency (which is caused by ETFDH gene mutations in the majority of the cases, or mutations in the ETFA and ETFB genes in a minority), mutations of ACAD9 gene, mutations of AIFM1 gene, mutations of the NDUFV1 and NDUFV2 genes. Therapeutic riboflavin administration has been tried in other neurological diseases, including stroke, multiple sclerosis, Friedreich's ataxia and Parkinson's disease. Unfortunately, the design of these clinical trials was not uniform, not allowing to accurately assess the real effects of this molecule on the disease course. In this review we analyse the properties of riboflavin and its possible effects on the pathogenesis of different neurological diseases, and we will review the current indications of this vitamin as a therapeutic intervention in neurology.

The authors report a peculiar disease, hitherto not described in the literature, observed in one asylum of r. Mlheimer'a. in Germany. The disease was clinically expressed by nausea, vomiting, dizziness, ptosis, diplopia, absence of pupil response to light and their dilation, Babinski's symptom, paraesthesias, nasal speech, difficulty in swallowing, cyanosis, Cheyne-Stokes breathing with good, regular pulse and normal temperature.

Objective: Acute bulbar palsy plus (ABPp) syndrome is a rare regional variant of Guillain-Barré syndrome (GBS) characterized by acute bulbar palsy combined with other cranial symptoms or ataxia without limb and neck weakness. We aim to investigate characteristics of ABPp syndrome and analyze its nosological position within the GBS spectrum.Methods: A patient with ABPp syndrome was reported, and previous case reports of patients who met the criteria for ABPp syndrome from the literature were reviewed.Results: A total of 28 patients were included in our study. Median age was 32 years. Most of the patients (78.6%) were from Asia, and 75.0% had preceding infection. The main accompanying symptoms were ophthalmoplegia (85.7%), facial palsy (60.7%), and ataxia (50.0%). There existed asymmetric weakness in the form of unilateral facial palsy (32.1%) and ptosis (3.6%). Approximately half of the patients had albuminocytological dissociation. All the tested patients were seropositive for antiganglioside antibodies, of which the two most common were immunoglobulin G (IgG) anti-GT1a (77.3%) and anti-GQ1b (59.1%) antibodies. Over one-third of the patients who underwent electrophysiological assessment showed subclinical neuropathy beyond cranial nerves. The outcome was generally favorable as 89.3% of patients made full recovery within 5 months.Conclusion: The hitherto largest case series of ABPp syndrome advances our understanding of this disease. Serologically, the presence of IgG anti-GT1a and anti-GQ1b antibodies predicts and contributes to the disease. Phenotypically, ABPp syndrome is more prone to be a separate subtype of GBS than overlap of distinct subtypes and has the potential to complement current diagnostic framework of GBS.

Background Cerebrotendinous xanthomatosis (CTX) is an inborn disorder of bile acid metabolism caused by deficiency of sterol 27-hydroxylase (CYP27A1) gene. CTX-related peripheral neuropathy has rarely been discussed in Chinese population. Here, we reported 6 CTX cases and performed a literature review focused on CTX with neuropathy to summarize its clinical and neurophysiological features. Methods All clinical data of 6 CTX cases were collected, and 21 reported Chinese CTX patients (including this study) were reviewed and summarized. Results Clinical manifestations of 6 CTX cases showed great heterogeneity. Cognitive decline, spastic paraplegia, cerebellar ataxia and advanced bulbar palsy were common neurological disorders, often accompanied by non-neurological signs like xanthomas, cataract, diarrhea and pes cavus. Dentate nuclei hyperintensity with or without hyposignal is a valuable MRI hallmark. Pooling our patients and literature review together, peripheral neuropathy was predominant sensorimotor demyelinating type in Chinese population, with an evident length dependent pattern and increased vulnerability in motor nerves. Demyelinating and axonal degeneration tend to exist in severe neuropathy. Three novel mutations including c.1055C>A; c.432T>G; c.472T>G were identified in CYP27A1 and predicted to be pathogenic. Oral CDCA therapy could ameliorate some of the existing symptoms and provide clinical stability, but it could not cease disease progression completely. Conclusions Our study broadens the phenotype and mutation spectrum of CTX. Patients with cognitive decline, spastic tetraparesis, cerebellar ataxia and bulbar palsy, should be highly suspicious of CTX even no xanthomas disclosed. Peripheral neuropathy was predominant sensorimotor demyelinating type in Chinese population, with mixed axonal and demyelinating type in severe cases. Three novel likely pathogenic mutations including c.1055C>A; c.432T>G; c.472T>G were identified in CYP27A1.

Background and purpose Cranial nerve palsy is occasionally present in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), but its prevalence, characteristics and relations with the CIDP subtypes have rarely been investigated. The aim of this study was to systematically assess cranial nerve involvement in typical and atypical CIDP. Methods Clinical data were reviewed in 132 consecutive patients with CIDP, including typical CIDP (n = 89), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) (n = 31), distal acquired demyelinating symmetric (DADS) (n = 9) and others (n = 3). Results The frequency of cranial nerve palsy was 11% in typical CIDP, 48% in MADSAM and 11% in DADS. Facial and bulbar palsy was most frequently present (9%), followed by ocular motor nerve palsy (5%). Bilateral involvement was seen in all typical CIDP and DADS patients, whereas 80% of MADSAM patients had unilateral palsy. The presence of cranial nerve involvement was associated with more severe limb muscle weakness in typical CIDP, but not in MADSAM. Cranial nerve palsy fully recovered in 90% of typical CIDP and in 67% of MADSAM patients. Conclusion Amongst the CIDP subtypes, cranial palsy is frequent and unilateral in MADSAM, and less frequent and bilateral in typical CIDP and DADS. In typical CIDP, facial and bulbar palsy reflects more severe and extensive inflammation.

The aim of the present study was to investigate the frequency and clinical features of Guillain-Barré syndrome (GBS) with hyperCKemia. We retrospectively identified 139 patients with GBS at 2 teaching hospitals in South Korea. We excluded patients with Miller-Fisher syndrome (n = 19), acute bulbar palsy (n = 3), and those whose serum creatine kinase (CK) levels were not measured (n = 45). Twelve of 72 patients (16.7%) had transient hyperCKemia, defined as serum CK ≥300 IU/L. The frequency of male sex and non-demyelinating electrodiagnostic features were higher in patients with hyperCKemia than those without. Transient hyperCKemia, occasionally seen in patients with GBS may be associated with the non-demyelinating subtype.

Sarcoidosis, which is a non-caseating granulomatous chronic inflammatory disease, can affect virtually any organ system, including the central nervous system (CNS). Very rarely, patients may present solely with neurosarcoidosis. It commonly presents with unilateral or bilateral seventh nerve palsy. Rarely it can present as dangerous progressive bulbar palsy and is a diagnostic and clinical challenge. We present a case of sarcoidosis with a unique presentation of isolated bulbar palsy. A 38-year-old male presented to the emergency with a sudden onset of dysphonia followed by dysphagia for both solids and liquids for one week and 5 kg weight loss in two months. The rest of the CNS exam was unremarkable. On labs, he had hypercalcemia and suppressed parathyroid hormone (PTH) intact. Detailed radiological investigations, lab tests, and lymph node biopsy helped confirm the diagnosis of neurosarcoidosis. The patient did not respond to first-line steroid therapy and hence received intravenous immunoglobulin (IVIG) subsequently with adequate response and complete neurologic recovery, confirmed by a follow-up visit.

Guillian-Barre Syndrome (GBS) typically presents as symmetrical ascending flaccid muscle weakness with areflexia, and with or without sensory symptoms. However, some patients may present atypically, and accordingly, different variants of GBS have been reported in the literature. Pharyngeal-cervical-brachial variant is one of the rare variants and is characterized by muscle weakness extending from the oropharyngeal and neck area to the proximal upper extremities. Many physicians and neurologists are unfamiliar about pharyngeal-cervical-brachial variant, which is often misdiagnosed as brainstem stroke, myasthenia gravis or botulism. Herein, we report a case of pharyngeal-cervical-brachial variant of GBS. To the best of our knowledge, this is the first reported case of pharyngeal-cervical-brachial variant of GBS in children from Nepal. A 14-year-old Asian male presented with weakness of bilateral upper limb, dysphagia, and nasal intonation of voice. A diagnosis of pharyngeal-cervical-brachial variant of GBS was made after excluding all other possible differentials and based on cerebrospinal fluid analysis and nerve conduction study. The patient improved following conservative management. Pharyngeal-cervical-brachial variant of GBS should always be considered in any patient presenting with symmetrical upper limb weakness and bulbar palsy. This is to ensure early diagnosis, treatment, and follow-up of the potential complications.

Background Alexander disease is a rare neurological disease characterized by progressive spastic quadriparesis and bulbar palsy. Moreover, certain patients with adult-onset Alexander disease were often misdiagnosed as other neurodegenerative disorders. Case presentation Herein, we report an adult a 58-year-old woman presented with typical parkinsonism with good levodopa-responsiveness. The patient’s dopamine transporter scanning showed significant striatal depletion, while her brain magnetic resonance imaging revealed bilateral tadpole shape of medulla oblongata and bilateral high signal intensity at both cerebellar dentate nuclei in T2-weighted images, suggesting the possibility of a genetic disorder beyond Parkinson’s disease. The patient’s genetic test resulted in known pathogenic glial fibrillary acidic protein variant, indicating Alexander disease. Conclusion This unique case highlights genetically diagnosed Alexander disease may present with clinical Parkinson’s disease.

Guillain Barre Syndrome (GBS) is characterised by acute onset ascending quadriparesis with areflexia. One of its rare variants is the Pharyngeal-Cervical-Brachial (PCB) variant which is characterised by acute weakness of the oropharyngeal, neck, and shoulder muscles with swallowing dysfunction. Here, the authors report a case of 57-year-old female, who presented with sudden onset dysphagia and nasal voice without having any limb weakness. Examination revealed reduced reflexes and weak palatal and pharyngeal muscles. Cerebrospinal Fluid (CSF) examination showed an albumino-cytological dissociation and nerve conduction studies revealed demyelinating motor polyneuropathy. A test for anti-GT1a antibody was positive. These findings were consistent with GBS. However, the patient presented only with bulbar involvement which is likely to be the milder form of the rare PCB variant. The patient recovered with plasmapheresis and was discharged in around three weeks. We conclude that GBS should be considered as differential diagnosis in a patient with isolated bulbar palsy.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a severe form of stiff-person spectrum disorder. We report a 59-year-old man who presented with progressive encephalomyelitis causing diplopia, bulbar palsy, severe dysautonomia, followed by stiffness and myoclonic cluster. Laboratory tests showed mild pleocytosis, with markedly elevated plasma levels of norepinephrine, epinephrine, and arginine vasopressin. Glycine-receptor antibodies were identified in both serum and CSF. Despite a poor response to methylprednisolone, immunoglobulins, and plasma exchange, α-blocker stabilized dysautonomia. Dysautonomia is presumed to be due to antibody-mediated disinhibited sympathetic hyperactivity; however, this case suggests that concomitant use of α-blocker with immunotherapy may ameliorate dysautonomia.

Brown-Vialetto-Van Laere syndrome (BVVL) is a rare, progressive neurodegenerative disease with fewer than 100 cases reported in the literature. It is characterized by pontobulbar palsy and sensorineural hearing loss.1 The age at onset varies from infancy to early adulthood, commonly presenting with cranial nerve VII–XII palsies and deafness. Other findings include gait ataxia, limb weakness, optic atrophy, epilepsy, and respiratory compromise.1 The genetic etiology of BVVL has recently been linked to mutations affecting the riboflavin transporter genes SLC52A2 and SLC52A3 , which code for human riboflavin transporters RFVT2 and RFVT3, respectively.2 Consequentially, several studies have reported improved clinical outcomes with riboflavin supplementation in patients confirmed to have mutations in the SLC52A2 and SLC52A3 genes.3–7 In this report, we describe a case of BVVL in a 6-year-old girl with dramatic visual recovery and neurologic improvement after delayed initiation of riboflavin supplementation. Consent was obtained from the child's parents.

A 20-year-old man presented with progressive dysphagia for 6 months to both liquids and solids with intermittent choking episodes. There was no nasal regurgitation, fatigability, or diurnal variation of dysphagia or difficulty in chewing. He had lost about 80 pounds in 6 months. He felt short of breath after walking for a short distance and climbing 2 flights of stairs and could not lie flat. He described muscle twitching in his face as well as arms and legs. He denied weakness of the upper or lower limbs, sensory symptoms, bladder or bowel problems, or uncontrollable laughing or crying. He had Lyme disease 5 years ago with left-sided facial palsy. The patient was of Hispanic ancestry and family history over 3 generations was negative for neuromuscular disorders, dementia, or prominent psychiatric disorders. On neurologic examination, he had a flat affect but normal bedside screening cognitive functions. His speech was nasal and his voice was hoarse. He had residual left lower motor neuron facial palsy. Cranial nerve V (motor and sensory) functions were normal. Palatal movements and gag reflex were normal. He had bilateral tongue atrophy, weakness, and fasciculations (video 1); perioral fasciculations were also present. There was mild lower limb spasticity and weakness in the following muscles: first dorsal interosseous (FDI) 4+/5, triceps 5−/5, deltoids 4+/5, gluteus maximus 4+/5, neck flexion 4/5. There was wasting of the periscapular muscles and FDI. There was no split hand phenomenon. Fasciculations were present in shoulder, biceps, thighs, and calves. Reflexes were 3+ and symmetrical at the biceps, triceps, brachioradialis, patellae, and ankles with flexor plantar responses; increased finger flexor and crossed adductor reflexes were present. Jaw jerk and snout reflexes were absent. Sensory and cerebellar examination results were normal.

Subacute neuroregression in association with raised neopterin and overexpression of interferon stimulated genes (ISGs) could indicate a type 1 interferonopathy. Here we describe a novel immunotherapy-responsive, clinico-immunological and imaging phenotype with evidence of innate immune activation. Three children (patient 1: 22-month-old boy; patient 2: 5-year-old girl; patient 3: 4-year-old girl) presented with asymmetric bilateral mixed dystonia and spasticity, regression in language (expressive more than receptive) and bulbar symptoms with no evidence of seizures. Symptoms evolved over several weeks to months. Brain MRI changes mimicked cerebral atrophy, initially asymmetric. CSF revealed raised neopterins. Blood RNA assay showed abnormal overexpression of ISGs and transient raised alanine aminotransferase (ALT). Importantly, all three children were treated with intravenous methylprednisolone and immunoglobulin with significant and sustained improvement in their motor and language function, and normalisation of imaging. Immune-mediated encephalitis can masquerade as subacute neuroregression.

Guillain–Barre Syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy and an important cause of acute flaccid paralysis (AFP) worldwide. Respiratory insufficiency requiring v entilator occurs in 30% of patients that prolong the hospital stay, leading to morbidity and mortality. There had been relatively few studies of Guillain-Barresyndrome in adults from North India. Objective: To evaluate clinical profile, epidemiological, laboratory and electro-diagnostic feature of patients with Guillain Barre Syndrome in adults and use of intravenous immunoglobulin (IVIg) in addition to supportive care. Materials and Methods: This was a prospective study of 50 patients with GBS admitted to our medicine department in rural tertiary care institution Dr.RPGMC Tanda. We studied the epidemiological, clinical, electrophysiological features and their outcome.Result In our study 50 cases were taken, motor weakness was the most common presenting feature. Antecedent illness was found in 48% of cases in the preceding two weeks, which included nonspecific illness, acute respiratory infection, diarrhea, and viral infection like chickenpox. At onset, sensory symptoms (pain and paresthesia) were noted in 16% of the cases and limb weakness in 77%. On admission, a majority (64%) was in Hughes neurological disability grading stage III-IV’ all had limb weakness at the peak deficit; autonomic disturbance was seen in 35.8%, and bulbar palsy in 6%. Duration of illness was less than three weeks in 60% of cases. The one patient had undergone repiratory distress and kept on ventilator for 23 days and survived. Conclusions: Male preponderance and motor weakness was the most common presenting illness and a majority achieved full recovery in our study. Although IVIg may be useful in the treatment of GBS, the key issue is excellent intensive care unit management.

Introduction Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired autoimmune disease of the peripheral nervous system. Its clinical presentation and excellent response to steroids is a hallmark to the disease entity. It is usually a straight forward diagnosis in typical cases. Atypical CIDP often is of diagnostic concern and has been a challenge for practising neurologists. Case description Here, we present a 56-year old female presented with isolated left palatal palsy preceded by a short febrile illness. Clinically consistent with post-infectious bulbar palsy, she was treated with intravenous pulse steroids and antibiotics. She had progressive disease and later developed quadriparesis with neck flexor weakness with progressive bulbar weakness and hypercapnic respiratory failure. Discussion and evaluation MRI whole spine with contrast showed nerve root enhancement. Nerve conduction studies of all four limbs and LP and CSF analysis were consistent with CIDP. She was treated with intravenous immunoglobulin (0.4 g/kg for five consecutive days). She showed mild improvement of symptoms initially and later had deterioration of symptoms within a week interval. She received two doses of Rituximab of 1 gram each within 3 weeks apart, after which she has gradual improvement. She was able to tolerate orally and able to walk without support following 1 month after treatment, and there were no further relapses except for the persistence of minor sensory symptoms after 6 months of follow-up. Conclusion Isolated cranial nerve involvement presenting as CIDP is a rare entity. Intravenous immunoglobulin and newer immunosuppressants like CD-20 monoclonal antibodies like rituximab have a significant role in the treatment.

Leigh syndrome (LS) is an early onset progressive neurodegenerative disorder with considerable clinical and genetic heterogeneities. Late-onset Leigh syndrome, i.e., onset after age of 2 years, is considered rare and often presents with atypical clinical features. We review the clinical features and imaging studies in a cohort of late-onset Leigh syndrome caused by mtDNA mutations. A total of 16 patients, 6 males and 10 females, were enrolled. The age at presentation was between 2 and 27 years of age. The first three clinical presentations found in our case series were ataxia, bulbar palsy, and pyramidal tract involvement, while disturbance of cognition and consciousness was less common. Six patients had both stroke-like episodes and seizures corresponding to the cortical lesions revealed on MRI. The most common lesion sites of basal ganglia and brainstem were putamen and midbrain, respectively. Dorsal aspects of the midbrain were the most vulnerable, especially periaqueductal region, and superior and inferior colliculus. Substantia nigra and red nuclei were involved less commonly. In our cohort, mutations of mtDNA in complex I were the commonest. In order of frequency, they were MT-ND3 (7/16), ND5 (3/16), ND6 (2/16), and ND1 (1/16). Causative mutations of MT-ATP6 were detected in the remaining three cases including 8993T>C, 9176 T>C, and 9185 T>C. Our study helps to define the types of clinical and neuroimaging finding in late-onset LS with the mutations of mtDNA. We expect to shed light on the identification of genotype–phenotype and genotype–neuroimaging correlations. On the other hand, our study highlights the importance of mtDNA mutations as a cause for LS, especially for late-onset cases.

We report a case of a male patient with a 19-year history of monoclonal and later polyclonal gammopathy who subsequently developed tetraparesis, bulbar palsy, and respiratory failure. Autopsy findings showed degeneration of the hypoglossal nuclei, prominent neuronal loss and atrophy in the anterior horn of the whole spinal cord despite the presence of mild astrocytosis, degeneration of the gracilis on one side, and infiltration of inflammatory cells, which included B cells and plasma cells in the anterior and posterior roots of the lumbar spinal cord, iliopsoas muscle, and perivascular area of the cervical cord. On immunostaining, cytoplasmic inclusions of phosphorylated transactivation response DNA-binding protein of 43 kDa were observed in the motor neurons and astrocytes of the hypoglossal nuclei and whole spinal cord. The final diagnosis was paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenstrom's macroglobulinemia.

Brown-Vialetto-van Laere syndrome is characterized by a progressive sensorimotor neuropathy, optic atrophy, hearing loss, bulbar dysfunction, and respiratory insufficiency. Mutations in SLC52A2 and SLC52A3, encoding riboflavin transporters RFVT2 and RFVT3, respectively, are the genetic basis of this disorder, often referred to as riboflavin transporter deficiency types 2 and 3, respectively. We present cases of both types of riboflavin transporter deficiency, highlighting the distinguishing clinical features of a rapidly progressive motor or sensorimotor axonal neuropathy, optic atrophy, sensorineural hearing loss, and bulbar dysfunction. One child presented with isolated central apnea and hypoventilation, not previously described in genetically confirmed Brown-Vialetto-van Laere, later complicated by diaphragmatic paralysis secondary to phrenic nerve palsy. Magnetic resonance imaging showed T2 hyperintensity in the dorsal spinal cord in 2 children, as well as previously unreported cervical nerve root enlargement and cauda equina ventral nerve root enhancement in 1 child. Novel homozygous mutations were identified in each gene-a NM_024531.4(SLC52A2):c.505C > T, NP_078807.1(SLC52A2):p.(Arg169Cys) variant in SLC52A2 and NM_033409.3(SLC52A3):c.1316G > A, NP_212134.3(SLC52A3):p.(Gly439Asp) variant in SLC52A3. Both treated children showed improvement on high-dose riboflavin supplementation, highlighting the importance of early recognition of this treatable clinical entity.