Three cases of adult-onset Brown-Vialetto-Van Laere syndrome: Novel variants in SLC52A3 gene and MRI abnormalities.

Brown-Vialetto-Van Laere syndrome is a rare, autosomal, recessive neurological condition caused by variants in the riboflavin transporter genes SLC52A2 and SLC52A3. Here, we report on three cases. Case 1 was a 35-year-old woman from a consanguineous family who presented with progressive deafness, subacute multiple cranial nerve impairments (III, VII, IX, XII), and MRI abnormalities (including as hypersignal from the cranial nerves). The patient was homozygous for a novel SLC52A3variant. Case 2 was the woman's brother, who presented similar symptoms. Case 3 was an 18-year-old woman experiencing progressive hearing loss, bilateral steppage gait and a cranial nerves impairment (VII and XII). MRI revealed hypersignal in the root nerves and cauda equina. A novel heterozygous variant in SLC52A3 was identified. A subacute history of polyradiculoneuropathy along with progressive deafness, cranial nerve impairment, and MRI abnormalities should raise suspicion for Brown-Vialetto-Van Laere syndrome.

Hypothalamic-Bulbar MRI Hyperintensity in Anti-IgLON5 Disease with Serum-Restricted Antibodies: A Case Report and Systematic Review of Literature.

BACKGROUND: Anti-IgLON5 disease is a rare neurodegenerative tauopathy that displays heterogeneity in clinical spectrum, disease course, cerebrospinal fluid (CSF) findings, and variable response to immunotherapy. Sleep disorders, bulbar dysfunction, and gait abnormalities are common presenting symptoms, and conventional brain MRI scanning is often unrevealing. OBJECTIVE: To provide a comprehensive overview of the literature and to assess the frequency of symptoms, MRI findings, and treatment response in patients with IgLON5 autoimmunity in the serum and CSF or restricted to serum. METHODS: We examined a 65-year-old woman with bulbar-onset IgLON5 disease with serum-restricted antibodies, and we also performed a systematic review of all confirmed cases reported in the English literature. RESULTS: We identified 93 patients, included our case. Clinical data were obtained in 58 subjects, in whom the most frequent symptoms were sleep-disordered breathing, dysphagia, parasomnias, dysarthria, limb or gait ataxia, stridor or vocal cord paresis, movement disorders, and postural instability. Distinct MRI alterations were identified in 12.5% of cases, as opposed to unspecific or unremarkable changes in the remaining patients. T2-hyperintense non-enhancing signal alterations involving the hypothalamus and the brainstem tegmentum were observed only in the present case. Inflammatory CSF was found in half of the cases and serum-restricted antibodies in 4 patients. Treatment with immunosuppressant or immunomodulatory drugs led to sustained clinical response in 19/52 patients. CONCLUSION: Anti-IgLON5 autoimmunity should be considered in patients with sleep disorders, bulbar syndrome, autonomic involvement, and movement disorders, and high-field brain MRI can be of diagnostic help.

The same cortico-efferent tract involvement in progressive bulbar palsy and in 'classical' ALS: A tract of interest-based MRI study.

BACKGROUND: There is an ongoing debate about the concept of restricted phenotypes of amyotrophic lateral sclerosis (ALS), including progressive bulbar palsy (PBP). OBJECTIVE: The study was designed to investigate specific white matter alterations in diffusion tensor imaging (DTI) data from PBP patients using a hypothesis-guided tract-of-interest-based approach (compared with 'classical' ALS patients and controls) to identify in vivo microstructural changes according to the neuropathologically defined ALS-related corticoefferent tract pathology. METHODS: DTI-based white matter mapping was performed both by an unbiased voxel-wise statistical comparison and by a hypothesis-guided tract-wise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 23 PBP and 23 ALS patients vs 23 matched controls. RESULTS: The analysis of white matter integrity demonstrated regional FA reductions along the CST and also in frontal and prefrontal brain areas both in PBP patients and ALS patients with additional regional FA reduction in the pons of the PBP group. In the tract-specific analysis according to the neuropathological ALS-staging pattern, PBP and ALS patients showed identical significant alterations of ALS-related tract systems when compared with controls. CONCLUSIONS: The DTI study including the tract-of-interest-based analysis showed the same microstructural corticoefferent involvement patterns in PBP patients as in ALS, which supports the hypothesis that PBP is a phenotypical variant of ALS.

Genetic, Radiologic, and Clinical Variability in Brown-Vialetto-van Laere Syndrome.

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.

Bulbar paralysis associated with Miller-Fisher syndrome and its overlaps in Chinese patients.

The study aimed to determine the incidence and the onset time of bulbar paralysis (BP) associated with Miller-Fisher syndrome (MFS) and its overlaps, to better understand the clinical characteristics among patients with MFS and its overlaps. Medical records from 48 patients with MFS and its overlaps were divided into two groups based on the presence (MFS-BP+) or absence (MFS-BP-) of BP. Their clinical features, laboratory and electrophysiological findings, neuroimaging data, and treatment plan were analyzed and compared between two groups. The incidence of BP associated with MFS and its overlaps was 48%. Eighty-two percent of the patients developed BP within 1 week after the onset of MFS and its overlaps. The cerebrospinal fluid (CSF) protein level in patients was higher in MFS-BP+ than in MFS-BP- group (67.69 ± 26.59 vs. 50.15 ± 20.44 mg/dl; P < 0.05). Frequencies of severe limb weakness, hypoglossal paralysis, disturbance of consciousness, and tracheal intubation required were also significantly higher in MFS-BP+ than in MFS-BP- group. Positive results of anti-GQ1b and anti-GT1b antibodies were all found in MFS-BP+ group. The prevalence of BP in MFS and its overlap was higher, the majority of BP occurred within 7 days after the onset of the disease, and early diagnosis of BP concurrence is helpful to decide the treatment plan.

Transient Isolated Lower Bulbar Palsy With Elevated Serum Anti-GM1 and Anti-GD1b Antibodies During Aripiprazole Treatment.

BACKGROUND: Transient bulbar palsy without involvement of the facial or extraocular muscles is a rare presentation. It is considered a form of cranial polyneuropathy, a variant of Guillain-Barré syndrome that is related to the autoimmune mechanisms induced by preceding infections or vaccinations. However, drug-induced cranial polyneuropathy has not previously been reported. We describe a boy with isolated bulbar palsy and positive serum antiganglioside antibodies during aripiprazole treatment. PATIENT DESCRIPTION: This 12-year-old boy was admitted with a seven-day history of dysarthria, tongue discomfort, and tinnitus. Three weeks before symptom onset, aripiprazole was added to the patient's medications for attention-deficit hyperactivity disorder. On examination, he showed curtaining of the pharyngeal wall, tongue fasciculation and deviation, and a weak gag reflex. Cranial magnetic resonance imaging suggested lower cranial nerve involvement. Serum anti-GM1 IgG and anti-GD1b IgG antibodies were positive. After stopping aripiprazole, his bulbar symptoms improved. However, on readministration of aripiprazole seven weeks later, dysarthria recurred and again resolved after stopping the drug. CONCLUSION: We describe the first patient with anti-GM1 IgG and anti-GD1b IgG antibodies-associated transient cranial polyneuropathy presenting as isolated bulbar palsy. These findings could be an adverse effect of aripiprazole treatment.

Frontal dysfunctions of ALS-PBP patients in relation to their bulbar symptoms and rCBF decline.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by progressive degeneration of spinal and bulbar motor neurons. However up to 50% ALS patients may also have cognitive dysfunction which has not been fully examined. METHODS: 35 ALS patients [23 patients presenting with limb-type ALS (ALS-limb) and 12 patients presenting with primary bulbar palsy (PBP)-type ALS (ALS-PBP)] and 5 Spinal and Bulbar Muscular Atrophy (SBMA) patients have participated. To assess cognitive function mini-mental state examination (MMSE), Hasegawa dementia scale-revised (HDS-R), and frontal assessment battery (FAB) were performed. Additionally the time to complete card flipping with a computerized touch panel-type screening test was also examined. To investigate regional cerebral blood flow (rCBF), single-photon emission computed tomography (SPECT) using a (99m)Tc labeled ethyl cysteinate dimer ((99m)Tc-ECD) were performed. Statistical image analysis was performed using the easy Z-score imaging system (eZIS). RESULTS: HDS-R and FAB scores were significantly lower in the ALS-PBP group than in age- and gender-matched control subjects or ALS-limb groups (p<0.01). The time to complete card flipping was significantly longer in the ALS-PBP group than in the control and ALS-limb groups (p<0.01). Although MMSE, HDS-R and FAB scores and the time to complete card flipping had no correlation with ALS functional rating scale-revised (ALSFRS-R) or Norris-limb scale scores, FAB score (r=0.63, p <0.01) and the time to complete card flipping (r=-0.66, p<0.01) were strongly correlated with Norris-bulbar score. The eZIS showed that rCBF of the frontal lobe was more severely declined in ALS-PBP patients than in ALS-limb patients (p<0.05). CONCLUSION: These results suggest a selective decline of frontal cerebral functions in the ALS-PBP group in relation to their bulbar symptoms and rCBF decline.

Pattern of glucose hypometabolism in frontotemporal dementia with motor neuron disease.

Frontotemporal dementia (FTD) often coexists with motor neuron disease (MND). To characterize glucose hypometabolism in patients with FTD with MND (FTD/MND), the authors compared the glucose metabolism of 8 patients with FTD/MND with that of 29 patients with FTD. All of the patients with FTD/MND showed glucose hypometabolism only in the frontal area, whereas most patients with FTD had hypometabolism in the frontal and temporal areas. FTD/MND also showed a more symmetric pattern of glucose hypometabolism than FTD.

Frontal lobe function in amyotrophic lateral sclerosis: a neuropsychologic and positron emission tomography study.

In this study the regional cerebral glucose utilization and the neuropsychological performance of patients with amyotrophic lateral sclerosis (ALS) was investigated. Special attention was given to neuropsychological tests thought to mirror frontal lobe dysfunction. The regional cerebral glucose utilization was studied in 18 patients using high-resolution positron emission tomography. Clinically all patients displayed upper and lower motor neurone signs. In ALS patients glucose metabolism was significantly reduced in the frontal and in the entire cortex compared with controls; no changes were seen in the cerebellum. Comprehensive neuropsychological assessment of ALS patients compared to a pair matched control group revealed mild frontal dysfunction which in part significantly correlated with reduced glucose metabolism in the cortex and subcortical structures. We conclude that in patients with ALS, glucose consumption is decreased in parts of the brain other than the motor cortex accompanied by mild neuropsychological deficits based on the tests employed in this study.

[A study of blink reflex in person with severely handicapped].

1) We evaluated blink reflex from 50 cases of severe handicapped. 7 cases (14%) had normal blink reflex. Abnormality of prolonged latency or no response of blink reflex was much more easily seen on R2 and R2' than R1, and dysfunction of spinal trigeminal complex or bulbar reticular formation might be existed in those cases. 2) We found abnormal blink reflex had some relationship with mental disturbance or bulbar function. Result of ABR and head CT also suggested that some kinds of cerebral factors might influenced to blink reflex of severe handicapped cases. 3) Blink reflex was one of the useful records for severe handicapped patients to evaluated underline pathogenesis of brain stem function.

Loss of striatal [76Br]bromospiperone binding sites demonstrated by positron tomography in progressive supranuclear palsy.

Using positron tomography and 76Br-labeled bromospiperone, a neuroleptic drug with high affinity for the dopamine (DA) receptors, we have estimated the specific binding of the radiotracer to striatal DA receptors in seven patients suffering from progressive supranuclear palsy. Compared with age- and sex-matched control subjects, we found a significant (p less than 0.02) decrease of the striatum-cerebellum uptake ratio in progressive supranuclear palsy patients, suggesting loss of striatal DA receptors. This in vivo study confirms recent postmortem data on progressive supranuclear palsy patients and provides an explanation for the lack of benefit from L-DOPA and DA agonists in this condition, despite reduced nigrostriatal dopaminergic function.

Subcortical dementia. Frontal cortex hypometabolism detected by positron tomography in patients with progressive supranuclear palsy.

The dementia associated with progressive supranuclear palsy (PSP) is considered to be subcortical because the cerebral cortex, unlike the subcortical structures, is usually free from major neuropathological lesions; the characteristic symptoms point to a dysfunction of the prefrontal lobe. The regional cerebral metabolic rate of glucose (rCMR Glu) was studied by positron emission tomography and 18F-fluoro-2-deoxyglucose18FDG in 6 patients presumed to have PSP and was compared with values found in 8 control subjects of similar age. The results obtained showed a highly significant rCMR Glu decrease in the prefrontal cortex of our patients. The loss of several subcortical afferents to prefrontal cortex may be responsible for the frontal cortical hypometabolism present in PSP.

CT findings in progressive supranuclear palsy.

Computed tomographic (CT) findings of three patients affected by progressive supranuclear palsy (PSP) are reported. The radiological picture consisted of atrophy of the midbrain and quadrigeminal plate, with prominent interpeduncular, crural, ambient, and quadrigeminal plate cisterns, and dilatation of the aqueduct and third ventricle. These features were not related to the duration of the illness and degree of neurological deficits. In the authors' opinion CT is useful in the differential diagnosis of PSP and other extrapyramidal disorders.

The operculum syndrome.

A 48-year-old man presented with signs of pseudobulbar palsy. On computed tomography (CT) he was found to have extensive tissue loss in the region of the sylvian fissure and insula bilaterally. This appearance on CT represents the radiological correlate to anatomic descriptions of the operculum syndrome, and is useful in distinguishing the condition from pseudobulbar palsy.