Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review

Despite expanding next generation sequencing technologies and increasing clinical interest into complex neurologic phenotypes associating epilepsies and developmental/epileptic encephalopathies (DE/EE) with movement disorders (MD), these monogenic conditions have been less extensively investigated in the neonatal period compared to infancy. We reviewed the medical literature in the study period 2000–2020 to report on monogenic conditions characterized by neonatal onset epilepsy and/or DE/EE and development of an MD, and described their electroclinical, genetic and neuroimaging spectra. In accordance with a PRISMA statement, we created a data collection sheet and a protocol specifying inclusion and exclusion criteria. A total of 28 different genes (from 49 papers) leading to neonatal-onset DE/EE with multiple seizure types, mainly featuring tonic and myoclonic, but also focal motor seizures and a hyperkinetic MD in 89% of conditions, with neonatal onset in 22%, were identified. Neonatal seizure semiology, or MD age of onset, were not always available. The rate of hypokinetic MD was low, and was described from the neonatal period only, with WW domain containing oxidoreductase (WWOX) pathogenic variants. The outcome is characterized by high rates of associated neurodevelopmental disorders and microcephaly. Brain MRI findings are either normal or nonspecific in most conditions, but serial imaging can be necessary in order to detect progressive abnormalities. We found high genetic heterogeneity and low numbers of described patients. Neurological phenotypes are complex, reflecting the involvement of genes necessary for early brain development. Future studies should focus on accurate neonatal epileptic phenotyping, and detailed description of semiology and time-course, of the associated MD, especially for the rarest conditions.

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Full Recovery From Cocaine-Induced Toxic Leukoencephalopathy: Emphasizing the Role of Neuroinflammation and Brain Edema

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/2324709619868266 ◽

2019 ◽

Vol 7 ◽

pp. 232470961986826 ◽

Cited By ~ 1

Author(s):

Edward C. Mader ◽

Alexander B. Ramos ◽

Roberto A. Cruz ◽

Lionel A. Branch

Keyword(s):

White Matter ◽

Time Course ◽

Brain Mri ◽

White Matter Lesions ◽

Psychomotor Retardation ◽

Full Recovery ◽

White Matter Disease ◽

Mri Findings ◽

Prognostic Information ◽

Toxic Leukoencephalopathy

Toxic leukoencephalopathy (TL) is characterized by white matter disease on magnetic resonance imaging (MRI) and evidence of exposure to a neurotoxic agent. We describe a case of cocaine-induced TL in which extensive white matter disease did not preclude full recovery. A 57-year-old man with substance abuse disorder presented with a 5-day history of strange behavior. On admission, he was alert but had difficulty concentrating, psychomotor retardation, and diffuse hyperreflexia. Brain MRI revealed confluent subcortical white matter hyperintensities with restricted diffusion in some but not in other areas. Electroencephalography (EEG) showed mild diffuse slowing. Blood tests were normal except for mild hyperammonemia. Urine screen was positive for cocaine and benzodiazepine but quantitative analysis was significant only for cocaine. Prednisone 60-mg qd was initiated on day 4, tapered over a 5-day period, and discontinued on day 9. He was discharged after 3 weeks. Cognitive function returned to normal 2 weeks after discharge. Five months later, neurologic exam and EEG were normal and MRI showed near-100% resolution of white matter lesions. TL has been attributed to white matter ischemia/hypoxia resulting in demyelination/axonal injury. The clinical, EEG, and MRI findings and time course of recovery of our patient suggest that cocaine-induced inflammation/edema resulted in TL but not in ischemic/hypoxic injury. While inflammation/edema may have regressed when cocaine was discontinued, we cannot exclude a role for prednisone in protecting the patient from the ischemic/hypoxic sequelae of inflammation/edema. MRI is indispensable for diagnosing TL but EEG may provide additional useful diagnostic and prognostic information.

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

Journal of Alzheimer s Disease ◽

10.3233/jad-201105 ◽

2020 ◽

pp. 1-9

Author(s):

Matteo Tagliapietra ◽

Emma Frasson ◽

Davide Cardellini ◽

Sara Mariotto ◽

Sergio Ferrari ◽

...

Keyword(s):

Systematic Review ◽

Sleep Disorders ◽

Movement Disorders ◽

English Literature ◽

Brain Mri ◽

Variable Response ◽

Mri Findings ◽

Comprehensive Overview ◽

Presenting Symptoms ◽

Vocal Cord Paresis

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.

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Diagnostic brain MRI findings in primary progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/135245850000600205 ◽

2000 ◽

Vol 6 (2) ◽

pp. 81-85 ◽

Cited By ~ 16

Author(s):

M Kremenchutzky ◽

D Lee ◽

G P A Rice ◽

G C Ebers

Keyword(s):

Multiple Sclerosis ◽

Age Of Onset ◽

Brain Mri ◽

Diagnostic Value ◽

Progressive Multiple Sclerosis ◽

Normal Brain ◽

Primary Progressive Multiple Sclerosis ◽

Mri Findings ◽

Primary Progressive ◽

Mri Scans

The clinical course of multiple sclerosis can be classified as relapsing from onset (relapsing-remitting), or progressive from onset (primary progressive -PPMS). These clinical phenotypes have been based on historical and clinical observations. It has been reported that PPMS patients tend to have quantitatively less MRI activity and disease burden. We evaluated the sensitivity and diagnostic value of conventional brain MRI scan in 143 PPMS patients. Brain MRIs were blindly evaluated to determine if they satisfied Paty and/or Fazekas diagnostic criteria. Patient were divided into those with typical atypical or normal scans. They satisfied brain MRI criteria in 92% cases. Findings included: 131 typical four atypical, and eight normal scans. All 12 non-typical scans' subject had spinal onset; spinal MRI scans were positive in four of seven cases. Sex, age of onset, site and number of symptoms involved at onset among those groups were not significantly different but accumulation of disability had a tendency to be slower in these few individuals with normal or atypical head MRI's. Although there may be quantitative differences in lesion activity/burden, MRI scanning in PPMS unexpectedly has diagnostic sensitivity very similar to that seen in RRMS. A normal brain MRI is unusual in PPMS patients.

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Brain MRI-findings in Ph - negative myeloproliferative disorders

Terapevticheskii arkhiv ◽

10.26442/00403660.2019.07.000329 ◽

2019 ◽

Vol 91 (7) ◽

pp. 29-34 ◽

Cited By ~ 2

Author(s):

M M Tanashyan ◽

A L Melikyan ◽

P I Kuznetsova ◽

A A Raskurazhev ◽

A A Shabalina ◽

...

Keyword(s):

Cerebrovascular Disease ◽

Sinus Thrombosis ◽

Cerebral Arteries ◽

Brain Mri ◽

Myeloproliferative Disorders ◽

Cerebral Venous Sinus Thrombosis ◽

Mri Findings ◽

Cerebral Lesions ◽

Cerebrovascular Pathology ◽

Underlying Mechanisms

Myeloproliferative disorders (MPD) are accompanied by a high proportion of thrombotic complications, which may lead to cerebrovascular disease (CVD). Aim. To describe MRI-findings in patients with Ph - negative MPD and evaluate any cerebrovascular disease. Materials and methods. We included 104 patients with Ph - negative MPD (age varied between 20 and 58) with clinical correlates of cerebrovascular pathology. Results. Brain MRI showed post - stroke lesions in 20% of patients (7 hemispheric infarcts due to thrombotic occlusion of one of the large cerebral arteries, 14 - cortical infarcts). 37 patients (36%) had vascular cerebral lesions. Cerebral venous sinus thrombosis occurred in 5 patients - in 7% (n=3) of patients with polycythemia vera and 5% (n=2) - in patients with essential thrombocythemia. The incidence of vascular cerebral lesions was associated with higher levels of the following: erythrocyte, platelet count, fibrinogen, and with the decrease in fibrinolytic activity, as well. Conclusion. The pioneering results of the study include the description and analysis of brain MRI-findings in patients with Ph - negative MPD. The underlying mechanisms of cerebrovascular pathology in these patients are associated with certain blood alterations (particularly, hemorheology) which present a major risk factor.

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Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

Brain Communications ◽

10.1093/braincomms/fcaa006 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Mendy M Welsink-Karssies ◽

Sacha Ferdinandusse ◽

Gert J Geurtsen ◽

Carla E M Hollak ◽

Hidde H Huidekoper ◽

...

Keyword(s):

Clinical Outcome ◽

Newborn Screening ◽

Clinical Outcomes ◽

Movement Disorders ◽

Brain Mri ◽

Primary Ovarian Insufficiency ◽

Ovarian Insufficiency ◽

Classical Galactosemia ◽

Intellectual Outcome

Abstract Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was <85 in 62%. Movement disorders were found in 17 (47%) of the 36 tested patients. In females aged 12 years and older, primary ovarian insufficiency was diagnosed in 12 (71%) of the 17 patients. Significant differences in N-glycan peaks were found between controls and patients. However, no significant differences in either N-glycans or galactose-1-phosphate levels were found between patients with a poor (intellectual outcome < 85) and normal intellectual outcome (intellectual outcome ≥ 85), and with or without movement disorders or primary ovarian insufficiency. The variant patients detected by newborn screening, with previously unknown geno- and phenotypes and currently no long-term complications, demonstrated significantly lower galactose-1-phospate levels than classical patients (P < 0.0005). Qualitative analysis of the MRI’s demonstrated brain abnormalities in 18 of the 21 patients, more severely in patients with a lower intellectual outcome and/or with movement disorders. This study demonstrates a large variability in clinical outcome, which varies from a below average intelligence, movement disorders and in females primary ovarian insufficiency to a normal clinical outcome. In our cohort of classical galactosemia patients, galactose-1-phosphate levels and N-glycan variations were not associated with clinical outcomes, but galactose-1-phosphate levels did differentiate between classical and variant patients detected by newborn screening. The correlation between brain abnormalities and clinical outcome should be further investigated by quantitative analysis of the MR images. The variability in clinical outcome necessitates individual and standardized evaluation of all classical galactosemia patients.

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Comparisons of clinical characteristics, brain MRI findings, and responses to epidural blood patch between spontaneous intracranial hypotension and post-dural puncture headache: retrospective study

BMC Neurology ◽

10.1186/s12883-021-02279-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Gha-Hyun Lee ◽

Jiyoung Kim ◽

Hyun-Woo Kim ◽

Jae Wook Cho

Keyword(s):

Intracranial Hypotension ◽

Dural Puncture ◽

Epidural Blood Patch ◽

Brain Mri ◽

Spontaneous Intracranial Hypotension ◽

Vein Of Galen ◽

Mri Findings ◽

Post Dural Puncture Headache ◽

Straight Sinus ◽

Blood Patch

Abstract Background Spontaneous intracranial hypotension and post-dural puncture headache are both caused by a loss of cerebrospinal fluid but present with different pathogeneses. We compared these two conditions concerning their clinical characteristics, brain imaging findings, and responses to epidural blood patch treatment. Methods We retrospectively reviewed the records of patients with intracranial hypotension admitted to the Neurology ward of the Pusan National University Hospital between January 1, 2011, and December 31, 2019, and collected information regarding age, sex, disease duration, hospital course, headache intensity, time to the appearance of a headache after sitting, associated phenomena (nausea, vomiting, auditory symptoms, dizziness), number of epidural blood patch treatments, and prognosis. The brain MRI signs of intracranial hypotension were recorded, including three qualitative signs (diffuse pachymeningeal enhancement, venous distention of the lateral sinus, subdural fluid collection), and six quantitative signs (pituitary height, suprasellar cistern, prepontine cistern, mamillopontine distance, the midbrain-pons angle, and the angle between the vein of Galen and the straight sinus). Results A total of 105 patients (61 spontaneous intracranial hypotension patients and 44 post-dural puncture headache patients) who met the inclusion criteria were reviewed. More patients with spontaneous intracranial hypotension required epidural blood patch treatment than those with post-dural puncture headache (70.5% (43/61) vs. 45.5% (20/44); p = 0.01) and the spontaneous intracranial hypotension group included a higher proportion of patients who underwent epidural blood patch treatment more than once (37.7% (23/61) vs. 13.6% (6/44); p = 0.007). Brain MRI showed signs of intracranial hypotension in both groups, although the angle between the vein of Galen and the straight sinus was greater in the post-dural puncture headache group (median [95% Confidence Interval]: 85° [68°-79°] vs. 74° [76°-96°], p = 0.02). Conclusions Patients with spontaneous intracranial hypotension received more epidural blood patch treatments and more often needed multiple epidural blood patch treatments. Although both groups showed similar brain MRI findings, the angle between the vein of Galen and the straight sinus differed significantly between the groups.

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Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0501 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Emily Breidbart ◽

Liyong Deng ◽

Patricia Lanzano ◽

Xiao Fan ◽

Jiancheng Guo ◽

...

Keyword(s):

Genetic Testing ◽

Exome Sequencing ◽

Large Scale ◽

Age Of Onset ◽

Family Members ◽

Ethnically Diverse ◽

Monogenic Diabetes ◽

Diabetes Diagnosis ◽

Pathogenic Variants ◽

Atypical Diabetes

Abstract Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

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Delayed post-hypoxic leukoencephalopathy: Case report

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.1654 ◽

2017 ◽

Vol 41 (S1) ◽

pp. s839-s839 ◽

Cited By ~ 1

Author(s):

M. Solerdelcoll Arimany ◽

M. Garriga ◽

E. Parellada

Keyword(s):

Neuropsychiatric Symptoms ◽

Brain Mri ◽

Clinical History ◽

Good Prognosis ◽

Mri Findings ◽

The Mean ◽

Competing Interest ◽

Weighted Sequences ◽

Direct Toxicity ◽

Progressive Cognitive Impairment

IntroductionDelayed post-hypoxic leukoencephalopathy (DPHL) is an underrecognized syndrome of delayed demyelination, where patients manifest neuropsychiatric symptoms after a period of 2–40 days of apparent recovery from a cerebral hypo-oxygenation episode.ObjectivesWe report a case of a patient who successfully recovered from an overdose of heroin, but then suffered a delayed abrupt neurological deterioration.AimsTo improve assessment and recognition of DPHL.MethodsAn adequate retrospective collection of clinical data and nonsystematic review of the literature was performed.ResultsA 43-year-old male with schizoaffective disorder who attempted suicide with an overdose of heroin, was successfully revived and return to his previously mental status, but 3 weeks after, he abruptly developed progressive cognitive impairment with akinetic mutism and ataxia. He was admitted to our acute psychiatric unit after brain CT and chemistry analyses were unremarkable. Brain MRI showed diffusely symmetric hyperintensity in the white matter (WM), pronominally the periventricular WM, on FLAIR and T2 weighted sequences. At 16 weeks postoverdose, he presented improvement both cognitive and motor symptoms, lasting deficits in frontal-executive functions.DiscussionDPHL is characterized by similar clinical and neuroimaging features regardless of the initial insult. The mean lucid interval coincides with the replacement half-life for myelin related lipids and proteins. Prolonged mild-to-moderate hypo-oxygenation of WM is thought to disrupt myelin turnover. It appears probable that these were responsible for DPHL in our patient rather than a direct toxicity.ConclusionDPHL can be diagnosed when clinical history, laboratory assessments and MRI findings are concordant. DPHL requires extensive support care and carries a relatively good prognosis.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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