Heterogeneous genetic patterns in bilateral perisylvian polymicrogyria: insights from a Finnish family cohort.

Bilateral perisylvian polymicrogyria is the most common form of regional polymicrogyria within malformations of cortical development, constituting 20% of all malformations of cortical development. Bilateral perisylvian polymicrogyria is characterized by an excessive folding of the cerebral cortex and abnormal cortical layering. Notable clinical features include upper motoneuron dysfunction, dysarthria and asymmetric quadriparesis. Cognitive impairment and epilepsy are frequently observed. To identify genetic variants underlying bilateral perisylvian polymicrogyria in Finland, we examined 21 families using standard exome sequencing, complemented by optical genome mapping and/or deep exome sequencing. Pathogenic or likely pathogenic variants were identified in 5/21 (24%) of families, of which all were confirmed as de novo. These variants were identified in five genes, i.e. DDX23, NUS1, SCN3A, TUBA1A and TUBB2B, with NUS1 and DDX23 being associated with bilateral perisylvian polymicrogyria for the first time. In conclusion, our results confirm the previously reported genetic heterogeneity of bilateral perisylvian polymicrogyria and underscore the necessity of more advanced methods to elucidate the genetic background of bilateral perisylvian polymicrogyria.

Long-term outcome of vestibular function and hearing in children with congenital cytomegalovirus infection: a prospective cohort study.

PURPOSE: Congenital cytomegalovirus infection (cCMV) is the most frequent nonhereditary cause for sensorineural hearing loss (SNHL) in children. Data on vestibular function in children with cCMV are, however, scarce, although some evidence for cCMV-associated vestibular dysfunction exists. In this prospective cohort study, we evaluated long-term vestibular function and hearing outcomes in a cohort of children with cCMV. METHODS: Participants were 6-7-year-old children with cCMV from a large population-based screening study. Controls were age and gender matched healthy children, who were CMV-negative at birth. Hearing was examined with pure tone audiometry. Definition of hearing loss was pure-tone average > 20 dB. Vestibular function was assessed using the video head impulse test that provides a measure of semicircular canal function. Definition of vestibular dysfunction was lateral semicircular canal gain < 0.75. RESULTS: Vestibular dysfunction occurred in 7/36 (19.4%) of children with cCMV and in 1/31 (3.2%) of controls (p = 0.060). SNHL was recorded in 4/38 (10.5%) of children with cCMV and in 0/33 of controls (p = 0.118). Hearing loss was unilateral in all cases. In cCMV group, the two children with bilateral vestibular dysfunction also had SNHL, whereas those with unilateral vestibular dysfunction (n = 5) had normal hearing. CONCLUSIONS: In this cohort of children with cCMV identified using newborn screening, vestibular dysfunction was more common than SNHL at 6 years of age. Vestibular dysfunction occurred both in children with and without SNHL. Based on these data, inclusion of vestibular tests in follow-up protocol of cCMV should be considered.

Duplication/triplication mosaicism of EBF3 and expansion of the EBF3 neurodevelopmental disorder phenotype.

Deleterious variants in the transcription factor early B-cell factor 3 (EBF3) are known to cause a neurodevelopmental disorder (EBF3-NDD). We report eleven individuals with EBF3 variants, including an individual with a duplication/triplication mosaicism of a region encompassing EBF3 and a phenotype consistent with EBF3-NDD, which may reflect the importance of EBF3 gene-dosage for neurodevelopment. The phenotype of individuals in this cohort was quite mild compared to the core phenotype of previously described individuals. Although ataxia tended to wane with age, we show that cognitive difficulties may increase, and we recommend that individuals with EBF3-NDD have systematic neuropsychological follow-up.

Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland.

The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case.

The spectrum of acute central nervous system symptoms during the treatment of childhood acute lymphoblastic leukaemia.

BACKGROUND: Children with central nervous system (CNS) toxicity during therapy for acute lymphoblastic leukaemia (ALL) are at risk for treatment modifications, long-term sequelae and even higher mortality. A better understanding of CNS symptoms and their complications improves the potential to prevent and treat them. METHODS: Patient files from 649 children treated with Nordic Society of Pediatric Hematology and Oncology ALL92 and ALL2000 protocols in Finland were reviewed retrospectively for any acute CNS symptom. Detailed data on symptoms, examinations and treatment of the underlying CNS complications were collected from the medical records. Disease-related and outcome data were retrieved from the Nordic leukaemia registry. RESULTS: Altogether, 13% (86) of patients with ALL had acute CNS symptoms. Most symptoms (64%) occurred during the first 2 months of therapy. Posterior reversible encephalopathy syndrome was the most frequent complication (4.5%). Cerebrovascular events were diagnosed in 10 cases (1.6%), while methotrexate-related stroke-like syndrome (SLS) was observed in only one patient (0.2%). CNS symptoms due to systemic or unclear conditions, especially sepsis, were important for differential diagnosis. CNS leukaemia was associated with CNS symptoms (hazard ratio [HR] = 4.03; P = .003), and epilepsy was a common sequel of CNS complications (19%). CONCLUSIONS: Acute CNS symptoms are common during ALL therapy, occurring mainly during the first 2 months of treatment. Patients with CNS leukaemia at diagnosis are at a higher risk for CNS toxicity. Despite intensive CNS-directed methotrexate treatment, SLS was diagnosed extremely rarely in our series.

Progressive Multifocal Leukoencephalopathy: Current Insights.

Cases of PML should be evaluated according to predisposing factors, as these subgroups differ by incidence rate, clinical course, and prognosis. The three most significant groups at risk of PML are patients with hematological malignancies mostly previously treated with immunotherapies but also untreated, patients with HIV infection, and patients using monoclonal antibody (mAb) treatments. Epidemiological data is scarce and partly conflicting, but the distribution of the subgroups appears to have changed. While there is no specific anti-JCPyV treatment, restoration of the immune function is the most effective approach to PML treatment. Research is warranted to determine whether immune checkpoint inhibitors could benefit certain PML subgroups. There are no systematic national or international records of PML diagnoses or a risk stratification algorithm, except for MS patients receiving natalizumab (NTZ). These are needed to improve PML risk assessment and to tailor better prevention strategies.

Novel DSP Spectrin 6 Region Variant Causes Neonatal Erythroderma, Failure to Thrive, Severe Herpes Simplex Infections and Brain Lesions.

Desmoplakin (DSP) and Desmoglein 1 (DSG1) variants result in skin barrier defects leading to erythroderma, palmoplantar keratoderma and variable [AQ4] other features. Some DSG1 variant carriers present with SAM syndrome (Severe dermatitis, multiple Allergies, Metabolic wasting) and a SAM-like phenotype has been reported in 4 subjects with different heterozygous DSP variants. We report here a patient with a novel DSP spectrin region (SR) 6 variant c.1756C>T, p.(His586Tyr), novel features of brain lesions and severe recurrent mucocutaneous herpes simplex virus infections, with a favourable response to ustekinumab. Through a review of reported cases of heterozygous variants in DSP SR6 (n = 15) and homozygous or compound heterozygous variants in DSG1 (n = 12) and SAM-like phenotype, we highlight phenotypic variability. Woolly hair, nail abnormalities and cardiomyopathy characterize patients with DSP variants, while elevated immunoglobulin E and food allergies are frequent in patients with DSG1 variants. Clinicians should be aware of the diverse manifestations of desmosomopathies.

Disseminated Scedosporium apiospermum central nervous system infection after lung transplantation: A case report with successful recovery.

Scedosporium species are fungal opportunistic pathogens frequently seen in chronic lung diseases such as in cystic fibrosis (CF). They can cause a wide spectrum of diseases mainly in immunodeficient patients. Invasive, disseminated infections with poor prognosis have been described after lung transplantation. We present a CF-patient with disseminated Scedosporium apiospermum infection after lung transplantation. The patient had skin, surgical wound, spinal cord, and brain involvements. She recovered fully after prolonged course of voriconazole treatment.

The Incidence and Predisposing Factors of John Cunningham Virus-Induced Progressive Multifocal Leukoencephalopathy in Southern Finland: A Population-Based Study.

BACKGROUND: The aim of this study was to assess the prevalence, incidence rate (IR), predisposing factors, survival rate, and diagnostic delay of progressive multifocal leukoencephalopathy (PML) across medical specialties. Another objective was to survey how PML diagnosis was made in the studied cases. METHODS: This is a cross-sectional retrospective observational study of PML cases across different medical specialties during 2004-2016 in the Finnish Capital Region and Southern Finland. Data were obtained from clinical records, clinical microbiology, pathology and radiology department records, and human immunodeficiency virus (HIV) quality register medical records. RESULTS: A total of 31 patients were diagnosed with PML. The prevalence of PML was 1.56 per 100 000 people and the IR was 0.12 per 100 000 individuals per year during 2004-2016. Hematologic malignancies (n = 19) and HIV/acquired immune deficiency syndrome (n = 5) were the most common underlying diseases, and all patients who had malignant diseases had received cancer treatment. Before PML diagnosis, 21 (67.7%) patients were treated with chemotherapy, 14 (45.2%) patients with rituximab, and 1 patient (3.2%) with natalizumab. Two patients (6.5%) had no obvious immunocompromising disease or treatment. Neither gender, age, first symptoms, previous medication, nor underlying disease influenced the survival of PML patients significantly. The 5-year survival rate was poor, at less than 10%. CONCLUSIONS: The majority of PML patients in our study had a predisposing disease or had immunosuppressive or monoclonal antibody therapy. In the future, broader use of immunosuppressive and immunomodulatory medications may increase incidence of PML among patients with diseases unassociated with PML. Safety screening protocols for John Cunningham virus and PML are important to prevent new PML cases.

Posterior Reversible Encephalopathy Syndrome: Risk Factors and Impact on the Outcome in Children With Acute Lymphoblastic Leukemia Treated With Nordic Protocols.

Posterior reversible encephalopathy syndrome (PRES) in children with acute lymphoblastic leukemia has been increasingly recognized as a clinicoradiological entity. Our aim was to describe the incidence of PRES in pediatric patients with ALL, identify its risk factors, and examine its prognostic importance. For this research, we conducted a systematic, retrospective review of the patient records in a population-based series of children with acute lymphoblastic leukemia (n=643) treated in Finland from 1992 to 2008. Of the patients with ALL, 4.5% (n=29) developed radiologically confirmed PRES, of which 28 cases occurred during induction. Hypertension (P=0.006; odds ratio [OR], 4.10, confidence interval [CI], 1.50-11.25), constipation (P=0.001; OR, 5.60; CI, 2.02-15.52), and >14 days of alkalinization (P=0.017; OR, 3.27; CI, 1.23-8.68) were significant independent risk factors for PRES. One-third of the patients developed epilepsy. Relapses occurred significantly more often in those patients with PRES (P=0.001), which was associated with worse overall survival (P=0.040; 5-year survival=75.9% [60.3%-91.4%] vs. 88.4% [85.8%-90.9%]). Using NOPHO-ALL 92/2000 protocols, PRES is a significant early complication of therapy in ALL, and was associated with a poorer prognosis and significant neurological morbidity.

Presenting features and imaging in childhood acute myeloid leukemia with central nervous system involvement.

Central nervous system (CNS) involvement in childhood acute myeloid leukemia (AML) can manifest as leukemic cells in the cerebrospinal fluid, a solid CNS tumor, or as neurological symptoms. We evaluated the presenting symptoms and neuroimaging findings in 33 of 34 children with AML and CNS involvement at diagnosis in the period 2000-2012 in Sweden, Finland, and Denmark. Imaging was performed in 22 patients, of whom 16 had CNS-related symptoms. Seven patients, including all but two with facial palsy, had mastoid cell opacification, considered an incidental finding. The frequent involvement of the mastoid bone with facial palsy warrants evaluation in larger series.

Role of neuroimaging in children with acute lymphoblastic leukemia and central nervous system involvement at diagnosis.

BACKGROUND: Each year approximately 200 children and adolescents are diagnosed with acute lymphoblastic leukemia (ALL) in the five Nordic countries, and 3% of these have central nervous system (CNS) involvement confirmed by leukemic cells in the cerebrospinal fluid (CSF) or neurological symptoms. We sought to determine the significance of neuraxis imaging in such patients. PROCEDURE: Magnetic resonance images of children aged 1-17.9 with CNS leukemia at diagnosis of ALL were centrally reviewed and clinical data were retrieved from the medical records and the Nordic leukemia registry. Patients were diagnosed in the period 2000-2012 in Sweden, Finland, or Denmark. RESULTS: The cohort comprised 1,877 patients, and 66 (3.5%) had CNS involvement. Forty-five percent (30/66) had CNS related symptoms. Symptoms included vomiting, facial palsy, headache, visual symptoms, and impaired hearing. CNS imaging was performed in 32 of 66 children (48%), and confirmed CNS involvement in 6 of 21 patients with symptoms (29%) and 5 of 11 (45%) without (P = 0.44). There was no difference in the overall survival between CNS-positive patients with and without signs of leukemic involvement by imaging (P = 0.53). CONCLUSIONS: Radiological imaging of asymptomatic children with CNS leukemia at diagnosis lacks clinical importance, but may be useful in patients with cranial nerve symptoms and negative CSF, as well as for follow-up. Imaging of symptomatic patients is warranted in order to exclude other causes underlying the symptoms.

Absence of Hikeshi, a nuclear transporter for heat-shock protein HSP70, causes infantile hypomyelinating leukoencephalopathy.

Genetic leukoencephalopathies are a heterogeneous group of central nervous system disorders with white matter involvement. In a Finnish patient, we identified a novel homozygous disease-causing variant in HIKESHI, c.11G>C, p.(Cys4Ser), leading to hypomyelinating leukoencephalopathy with periventricular cysts and vermian atrophy. A founder Ashkenazi-Jewish disease-causing variant recently linked Hikeshi and its heat-shock protective function to leukoencephalopathy. In our patient, clinical features of lower limb spasticity, optic atrophy, nystagmus, and severe developmental delay were similar to reported patients. Additional features included vermian atrophy, epileptic seizures, and an ovarian tumor. Structural modeling and protein analyses revealed that modified interactions inside Hikeshi's hydrophobic pockets induce protein instability. The patient's cells showed impaired nuclear translocation of HSP70 during heat shock, and decreased ERO1-Lα, an endoplasmic reticulum (ER) oxidoreductase. Overall, we show that: (1) the clinical spectrum associated with Hikeshi deficiency extends to leukoencephalopathy with vermian atrophy and epilepsy; (2) the cellular disease process involves both nuclear chaperone and ER functions.

[The many faces of neurosyphilis]. / Neurosyfiliksen monet kasvot.

Syphilis is an infectious disease caused by Treponema pallidum. We describe two patients with chronic syphilis causing neurosyphilis. The first had had several brain infarctions due to the presence of meningovascular syphilis. Second patient suffered from motor and psychiatric symptoms caused by syphilis. The symptoms of our patients were alleviated by antibiotic therapy. Recognition of the multifaceted symptom picture of syphilis is increasingly important, because the occurrence of the disease has increased in our country over the last few decades. An early enough treatment can prevent permanent disability of the patient.

Hypoperfusion of an entire cerebral hemisphere - stroke or postictal deficit?

The clinical differential diagnosis between ischemic stroke and postictal deficit is sometimes challenging. If the clinical presentation is inconclusive, perfusion imaging can help to identify stroke patients for thrombolysis therapy. However, also epileptic phenomena may alter cerebral perfusion. Hypoperfusion spreading beyond the borders of cerebrovascular territories is usually considered suggestive of an etiology other than stroke. We present a patient whose clinical symptoms suggested a postictal deficit rather than an acute stroke. CT perfusion imaging showed hypoperfusion of the entire left cerebral hemisphere covering all vascular territories. CT angiography revealed occlusions in the ipsilateral internal carotid artery and in the circle of Willis as the cause of the global hypoperfusion. The patient was treated with i.v. thrombolysis and recovered with moderate disability. This is the first description of hyperacute ischemia of an entire cerebral hemisphere and its treatment with thrombolysis. It demonstrates the potential of modern neuroimaging in identifying atypically presenting strokes and shows that i.v. thrombolysis can be effectively and safely used to treat such potentially fatal insults.

Clinical characteristics of patients with Epstein Barr virus in cerebrospinal fluid.

BACKGROUND: The role of Epstein-Barr (EBV) virus in central nervous system (CNS) infections is not fully resolved. It is clearly associated with lymphoproliferative disease of immunosuppressed persons, and may cause encephalitis. METHODS: We reviewed the medical records, imaging and laboratory findings of all patients EBV DNA PCR positive in cerebrospinal fluid (CSF) during 2000 to 2009 in the Helsinki University Central Hospital. RESULTS: We identified 32 patients with EBV DNA in CSF. 11 had history of allogeneic hematopoietic stem cell transplantation, 7 solid organ transplantation and 5 HIV/AIDS. 5 patients had no preceding immunodeficiency.In 8 of the cases, another pathogen was identified in CSF. These were M. tuberculosis (2), T. gondii (2), Aspergillus (1), Herpes simplex virus 1 (1), C. neoformans (1) and Human herpesvirus 6 (1). Altogether in 15/32 (47%) of the cases the clinician had a strong suspicion of cause other than EBV for the patients' CNS symptoms/findings.Of note, 7 of 11 (64%) patients with stem cell transplantation had encephalitis (univariate odds ratio 5.6; confidence Interval 1.1-27.4). Of these 6 had no other pathogen identified. CONCLUSIONS: EBV DNA was often found together with other microbial findings in CSF of immunocompromised patients. EBV seems to be associated with encephalitis in stem cell transplant recipients.

Magnetoencephalographic Abnormalities in Creutzfeldt-Jakob Disease: A Case Report.

Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disease with no effective therapy available. We recorded spontaneous magnetoencephalography and auditory evoked fields (AEFs) from a male patient with a rapidly progressive memory disorder, ataxia and myoclonus. Post-mortem examination confirmed sporadic CJD. Sources of the abnormal slow wave activity were localized with a beamformer software. Sources of sharp transients and AEFs were modeled with equivalent current dipoles. The estimated sources of spontaneous activity abnormalities were more dominant in the left hemisphere, in line with left-dominant abnormalities in diffusion-weighted MRI. Sources of AEFs were found in both temporal lobes. Magnetoencephalography measurements on CJD patients are feasible, and provide efficient means for localizing abnormal cortical activity in CJD.