A review and recommendations for oral chaperone therapy in adult patients with Fabry disease.

Fabry disease (FD) is a rare, X-linked lysosomal storage disorder affecting both males and females caused by genetic abnormalities in the gene encoding the enzyme α-galactosidase A. FD-affected patients represent a highly variable clinical course with first symptoms already appearing in young age. The disease causes a progressive multiple organ dysfunction affecting mostly the heart, kidneys and nervous system, eventually leading to premature death. Disease-specific management of FD includes enzyme replacement therapy with agalsidase α and ß or pharmacological oral chaperone migalastat. Migalastat is a low-molecular-mass iminosugar, that reversibly binds to active site of amenable enzyme variants, stabilizing their molecular structure and improving trafficking to the lysosome. Migalastat was approved in the EU in 2016 and is an effective therapy in the estimated 35-50% of all patients with FD with amenable GLA gene variants. This position statement is the first comprehensive review in Central and Eastern Europe of the current role of migalastat in the treatment of FD. The statement provides an overview of the pharmacology of migalastat and summarizes the current evidence from the clinical trial program regarding the safety and efficacy of the drug and its effects on organs typically involved in FD. The position paper also includes a practical guide for clinicians on the optimal selection of patients with FD who will benefit from migalastat treatment, recommendations on the optimal selection of diagnostic tests and the use of tools to identify patients with amenable GLA mutations. Areas for future migalastat clinical research have also been identified.

Atypical clinical presentation of glioblastoma mimicking autoimmune meningitis in an adult.

Glioblastoma (GBM) is the most malignant type of glial tumor associated with a very unfavorable prognosis. Typical radiological features of GBM include the presence of a tumor with irregular contrast-enhancing margins and central necrosis surrounded by a wide area of vasogenic edema. Here, we presented an atypical clinical presentation of GBM mimicking autoimmune meningitis. A 69-years-old previously healthy male was admitted to the emergency room due to signs of increasing cognitive impairment, weight loss, changes in behavior, difficulty in walking, and prolonged episodes of nausea over the past month. An magnetic resonance imaging (MRI) brain scan revealed hyperintense changes of the periventricular area surrounding brain ventricles in T2 and FLAIR, and post-contrast leptomeningeal enhancement and thickening of meninges involving cerebellar sulci. An additional MRI scan of the cervical spine showed an in-core contrastenhancing lesion on the C7-Th1 level as well as leptomeningeal thickening and post-contrast-enhancement around the spinal cord. Various laboratory tests and two stereotactic biopsies were performed with no essential to diagnosis clinical findings. A couple of months after first hospital admission, the patient died. Post-mortem examination of the brain revealed numerous foci of abnormal tissue inside the subarachnoid space, lateral ventricles, and cerebral aqueduct. Histological examination showed diffuse malignant astroglial neoplasm, and diagnosis of glioblastoma NOS WHO G IV was established. Even though the appearance of usual GBM is widely recognizable, one must bear in mind the possibility of unusual presentation. The presented case highlights the diagnostic difficulties of diffuse glioblastoma with atypical clinical presentation.

Ultrastructure of mitochondria and damage to small blood vessels in siblings with the same mutation in the NOTCH 3 and coexisting diseases.

We performed ultrastructural studies of mitochondria and evaluated the appearance of small blood vessels of three middle-aged siblings affected by the same mutation in the NOTCH3 gene, causing CADASIL. CADASIL pathognomonic features include granular osmiophilic material (GOM), which we observed. GOMs were located in damaged and thickened basement membranes (BM) of capillaries and arterioles. Our patients were also burdened by type II diabetes (first patient), impaired glucose metabolism (second patient), and hypertension (third patient). The ultrastructure of the capillaries in the first and second patients differed from the third patient. In diabetes/impaired glucose metabolism patients (first and second patients), we observed: pathologies of mitochondria in damaged endothelium and pericytes of capillaries; extremely thickened (BM) with visible remains of vascular cells; well-preserved GOMs anchored in the rebuilt capillary extracellular matrix. We identified degenerated or vestigial small blood vessels of skeletal muscles in the first patient. The capillary damage in the third patient (with hypertension) was milder compared to the diabetes/impaired glucose metabolism patients. We conclude that in patients with a mutation in the NOTCH3 gene, the co-occurrence of diseases such as type II diabetes/impaired glucose metabolism can cause a multiplication the damages to small blood vessels by modifying/masking the pathogenesis of CADASIL.

Considerations for Home-Based Treatment of Fabry Disease in Poland during the COVID-19 Pandemic and Beyond.

Current therapy for Anderson-Fabry disease in Poland includes hospital or clinic-based intravenous enzyme replacement therapy with recombinant agalsidase alpha or beta, or oral pharmacological chaperone therapy with migalastat. Some countries around the world offer such treatment to patients in the comfort of their own homes. The 2020-2021 COVID-19 pandemic has pushed global healthcare providers to evolve their services so as to minimize the risk of COVID-19 exposure to both patients and providers; this has led to advances in telemedicine services and the increasing availability of at-home treatment for various procedures including parenteral drug administration. A total of 80% of surveyed Anderson-Fabry disease patients in Poland would prefer home-based treatment, which would be a safe and convenient alternative to clinic-based treatment if patient selection is based on our proposed algorithm. Our recommendations for home-based treatments appear feasible for the long term care of Anderson-Fabry disease patients during the COVID-19 pandemic and beyond. This may also serve as a basis for home-based treatment programs in other rare and ultra-rare genetic diseases.

Is home-based therapy in Fabry disease the answer to compelling patients' needs during the COVID-19 pandemic? Survey results from the Polish FD Collaborative Group.

BACKGROUND: Fabry disease (FD) is an X-linked disorder related to a deficiency of the lysosomal enzyme alpha-galactosidase A. In Poland, enzyme replacement therapy (ERT) for FD is offered by the National Health Fund only at selected hospital infusion centers. Patients with FB are considered at a high risk of developing complications from COVID-19. Some patients omitted infusions due to fear of infection or outbreaks in hospitals. Lack of alternative infusion sites hampered the situation. OBJECTIVES: To analyze the impact of the SARS-CoV-2 pandemic on FD patients, especially their fears and expectations, the Polish FD Collaborative Group collaborated on a survey project. MATERIAL AND METHODS: Between September and November 2020, we distributed a customized survey exploring expectations and fears among FD subjects. RESULTS: Fifty-five individuals (35 receiving ongoing ERT) from different FD centers completed the study. The median age was 40 years [IQR 25; 50], and gender distribution was almost equal (27 F; 28 M). One-fourth of FD patients reported severe disability limiting transportation for infusions that, in the opinion of the other 25% of responders, consumed >4 h. Forty-four (80%) of all would prefer home infusions performed by a nurse (n = 37, 67.3%) or by a trained non-medical person (n = 7, 12.7%), while 8 (14.5%) patients would choose a local hospital. As expected, transportation time (in one direction) was longer in those preferring home infusions (89.4 ±63 vs 36.2 ±67 min; p = 0.02). Also, those with more severe FD manifestation would prefer home infusions to treatment in FD centers (p = 0.03). The vast majority of respondents (n = 46; 83%) would not change their preferences after pandemic termination. CONCLUSIONS: To maintain ERT, FD patients prefer home infusions or those given in the nearest hospital, especially during a pandemic.

Morphological and ultrastructural changes in Herpes simplex encephalomyelitis: an attempt to determinate the etiological factor.

Herpes simplex encephalomyelitis (HSE) is a rare disease with a high mortality rate. Correct diagnosis is established on the basis of the combination of the clinical and investigative features. Unfortunately, precise diagnosis remains difficult due to several clinical similarities and false negative or inconclusive results of diagnostic tests. Here, we present two cases of HSE together with the morphological and ultrastructural picture. The first case was a 45-year-old man with acute symptoms of encephalitis, and the other one was a 28-year-old woman presenting subacute encephalomyelitis. Both cases had negative serologic and molecular results for Herpes simplex in the blood and cerebrospinal fluid. Brain and spinal cord samples taken from both cases were stained typically with histological and immunohistochemical methods and small tissue fragments were examined with the transmission electron microscope (TEM). Microscopic examination confirmed viral encephalomyelitis in both cases. An electron micrograph showed typical intranuclear viral particles inside of damaged neurons, which together with topography of brain and spinal cord changes suggest HHV-1/HHV-2 in the first case and/or HHV-3 in the other case. Thus, morphological and ultrastructural examinations may be a useful tool to set up correct diagnosis and help to determine the pathogenic factor in patients suspected of viral encephalomyelitis.

High incidence and clinical characteristics of fibromuscular dysplasia in patients with spontaneous cervical artery dissection: The ARCADIA-POL study.

The association between fibromuscular dysplasia (FMD) and spontaneous cervical artery dissection (SCeAD) has been recognized, but the available evidence on this relationship is scant. Therefore, the main goal of our study was to systematically evaluate FMD frequency, clinical characteristics and vascular bed involvement in patients with SCeAD. Among 230 patients referred to the ARCADIA-POL study, 43 patients (mean age 44.1 ± 8.9 years; 15 men and 28 women) with SCeAD were referred. Also, 135 patients with FMD were compared to patients with and without SCeAD. Patients underwent: ambulatory blood pressure measurements, biochemical evaluation, echocardiographic examination, and whole body computed tomographic angiography. FMD changes were found in 39.5% of patients with SCeAD. There were no differences in clinical characteristics between patients with SCeAD and FMD and those without FMD, except for a tendency towards a higher female ratio in SCeAD patients with FMD. There were no differences in other parameters describing target organ and SCeAD characteristics. Patients with SCeAD and FMD compared to those without SCeAD were characterized by a lower frequency of hypertension and a higher frequency of hyperlipidemia and history of contraceptive hormone use. Our study indicates a high incidence (39.5%) of FMD in subjects with SCeAD. Since there are no distinctive discriminating factors between patients with SCeAD and FMD and those without FMD, FMD should be suspected in all patients with SCeAD.

Intracerebral hemorrhage in the context of cerebral amyloid angiopathy and varied time of onset of cerebral venous thrombosis: a case report.

In patients with cerebral venous thrombosis (CVT) the incidence of intracerebral hemorrhage (ICH) is estimated at about 37% and subarachnoid hemorrhage (SAH) at 1% of patients. A case with coincident occurrence of ICH, SAH and CVT in a patient with cerebral amyloid angiopathy (CAA) is reported. A 79-year-old woman was admitted to the Neurological Department after the occurrence of generalized seizures, the first in her life. On admission she was unconscious with right hemiparesis and deviation of eyes to the left. On computed tomography (CT) scan many hemorrhagic infarcts were present in the frontal, parietal, temporal and left occipital lobes. Angio-CT revealed thrombosis in the right transverse sinus, right internal carotid vein and superior sagittal sinus. Her state slowly deteriorated. She died after 6 days. Neuropathologically, many hemorrhagic infarcts were observed in cortical regions in the vicinity of veins with thrombosis and in the white matter. The varied time of onset of thrombosis of the right sigmoid sinus, right superior petrosal sinus, superior sagittal sinus, right transverse sinus and the proximal part of the right internal carotid vein was confirmed. cerebral amyloid angiopathy in brain vessels was diagnosed. Subarachnoid hemorrhage is a very uncommon presentation of CVT and may coexist with CAA. We can only speculate that CAA may have an effect on vein destruction and can promote cerebral vein thrombosis and in consequence also predispose to intracerebral hemorrhage and subarachnoid hemorrhage. The most probable cause of extensive thrombosis was a coagulation disorder.

Novel mutation of the NOTCH3 gene in a Polish family with CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small blood vessels disease caused by mutations in the gene encoding the neurogenic locus notch homolog protein 3 (NOTCH 3). We present a Polish family with a previously unreported novel mutation in exon 12 c.1851C>C/G of the NOTCH3 gene and varying disease expression. One of the two family members with the confirmed mutation presented with all the main CADASIL symptoms; while, his affected father was nearly asymptomatic. Both family members had epilepsy, coronary artery disease, and abdominal aorta aneurysm. Our observation confirms there is phenotypic variability in CADASIL not only between, but also within, families carrying the same mutation.

Carotid intima media thickness and blood biomarkers of atherosclerosis in patients after stroke or myocardial infarction.

AIM: To test if circulating levels of markers of inflammation, endothelial function, and chronic infections, as well as association between these markers and carotid intima media thickness (CIMT), depend on the stage of atherosclerosis expressed as a history of a major vascular event. METHODS: The associations were analyzed separately in 75 healthy controls, 79 patients 3-6 months after the first-ever non-cardioembolic ischemic stroke (IS), and 37 patients 3-6 months after the first-ever myocardial infarction (MI). Data were collected prospectively in 2005. We measured high sensitivity C-reactive protein (hs-CRP), procalcitonin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), serum level of immune complexes (IC), and identified antibodies against Herpes simplex virus type 1 (HSV), Cytomegalovirus, Chlamydia pneumonia, and Helicobacter pylori. Correlations with CIMT were determined using Pearson R and verified after adjustment for age, sex, hypertension, diabetes, and statin therapy. RESULTS: Median ICAM-1 concentration was significantly lower in controls than in post-IS patients (188 µg/L vs 215 µg/L), and significantly lower in post-IS patients than in post-MI patients (215 µg/L vs 260 µg/L). Control patients also had significantly lower IC level (0.03 U/L) and HSV antibody index (6.0) compared to both post-IS (0.6 U/L, 9.6) and post-MI (0.4 U/L, 9.2) patients. CIMT was correlated with age (Pearson R=0.38, P=0.001) in the control group, immune complexes (R=0.26, P=0.023) in the post-IS group, and with hs-CRP (R=0.40, P=0.017) in the post-MI group. These correlations were confirmed using multiple regression analysis. CONCLUSIONS: Our study supports linear correlations between CIMT and IC and hs-CRP levels. However, these associations seem to depend on the type of vascular burden.

APOE ϵ 2 allele is an independent risk factor for vulnerable carotid plaque in ischemic stroke patients.

BACKGROUND AND AIMS: The data about apolipoprotein E gene (APOE) genotype and the risk of stroke are inconsistent. The APOE genotype is expected to influence the development of carotid plaques. Our aim was to look for association between APOE genotype and carotid plaque morphology in ischemic stroke patients. METHODS AND RESULTS: Data of ischemic stroke patients was collected prospectively for 2 years. The degree of stenosis and plaque echogenicity and surface were assessed with ultrasound. Subsequent APOE genotypes were compared: APOE ϵ 3/ϵ 3 (E3--reference), APOE ϵ 2/ϵ 3 (E2 group) and APOE ϵ 3/ϵ 4, APOE ϵ 4/ϵ 4 (E4 group). We included 388 patients with acute ischemic stroke. Patients in E2 group had more often hypoechogenic, ulcerated plaques and severe stenosis comparing to E3 patients. On logistic regression analysis, ϵ 2 genotype remained an independent risk factor for vulnerable carotid plaque (OR  =  2.3 for <60% stenosis and OR  =  2.7 for ≥60% stenosis; 95% CI). CONCLUSIONS: This study suggests that ϵ 2 allele is an independent risk factor for echolucent and ulcerated carotid plaque.

Positivity of serum "classical" onconeural antibodies in a series of 2063 consecutive patients with suspicion of paraneoplastic neurological syndrome.

This study determined the prevalence of classical onconeural Ab in a series of 2063 consecutive patients that were investigated because of suspicion of PNS as well as evaluated individual onconeural Ab in relationship to the clinical spectrum of associated neurological syndromes and tumor types detected in 70 patients finally diagnosed with PNS. We conclude that detectability of onconeural Ab is low among patients suspected with PNS. Specification of Ab is helpful in defining a neurological syndrome as paraneoplastic as well as in searching of underlying tumor. The success in tumor screening depends on the type of onconeural Ab.

Echolucent internal carotid artery plaques are a risk factor for stroke.

BACKGROUND AND PURPOSE: Atherosclerotic changes in carotid arteries are responsible for 10-20% of strokes. The aim of our study was to examine how the ultrasonic morphology of carotid arteries influences the occurrence of ischaemic stroke (IS). MATERIAL AND METHODS: Ultrasonography of the carotid arteries was performed with a 7-MHz duplex-type scanner Acuson 128XP/10C. We examined 200 consecutive acute IS patients and 100 sex- and age-matched control subjects. Morphology of atheromatic plaques was evaluated with the assessment of degree of stenosis, surface regularity and echogenicity of the plaques. The predictive value of potential prognostic variables in the assessment of the risk of IS was tested using regression models. RESULTS: The most frequent site of atherosclerotic changes was the internal carotid artery (ICA) (right ICAs: 34.5% in IS group vs. 19% in controls, p=0.005; left ICAs: 26.5% vs. 16%, p=0.04). Plaques in ICAs were significantly more severe in IS patients than in controls. Echolucent plaques were observed in the IS group in 11% of right and 5.5% of left ICAs, whereas in controls we found echolucent plaques in only 2% in left ICAs. IS occurrence was independently predicted by: hypertension, congestive heart failure, current smoking status, haemodynamically significant and echolucent plaques in ICAs. CONCLUSIONS: Echolucent plaques in ICAs are an independent risk factor for ischaemic stroke even if they have no impact on haemodynamics of blood flow. Clear characterization of plaques in CAs, especially vulnerable plaques, together with estimation of the degree of stenosis, may improve the selection of patients for invasive secondary prevention methods.

Granular cell astrocytoma. A case report with immunohistochemical and ultrastructural characterization.

Granular cell astrocytoma (GCA) is an uncommon type of granular cell tumours (GCTs) in the central nervous system. Granular cells in these tumours are of enigmatic origin. We report a case of cerebral GCA in a 59-year-old man who suffered from diabetes and Addison-Biermer disease. The tumour was localized in the left parietal lobe. Microscopically, the tumour was almost entirely composed of large, polygonal cells with round to oval, granular eosinophilic, PAS-positive cytoplasm. The nuclei were located centrally or eccentrically and sometimes exhibited nucleolar vacuoles. The tumour cells were arranged in nests surrounded by blood vessels and connective tissue. Immunohistochemically, the granular tumour cells were reactive for GFAP and vimentin. They were intensively stained for ubiquitin and some of them were reactive for CD68. Moreover, a lot of stromal cells expressed CD68 reactivity. Ultrastructurally, most tumour cells were round or oval with only a few or without filaments. Their cytoplasm was filled with electron-dense granular material limited by a single membrane and autophagic vacuoles. Another type of tumour cells, present in a significantly lower number, revealed abundant cytoplasm with numerous intermediate filaments, swollen rough endoplasmic reticulum, mitochondria and a few clusters of granular material. Cells with numerous condensed electron-dense, bizarrely-shaped mitochondria and few filaments were occasionally observed. Among granular cells, macrophages with vacuoles and/or lamellar structures were visible. In our case, both immunohistochemical and ultrastructural analysis supported astroglial origin of the granular cell tumour.