Leonardo Modesti Vedolin

Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression

In mucopolysaccharidosis I, deficiency of α‐L‐iduronidase can cause spinal cord compression (SCC) due to storage of glycosaminoglycans (GAGs) within the cervical meninges. As intravenous enzyme replacement therapy (ERT) is not likely to provide enzyme across the blood–brain barrier, standard treatment for this complication is usually surgical, which has a high morbidity and mortality risk. We report on the use of intrathecal (IT) laronidase in a MPS I patient with SCC who refused the surgical treatment. Assessments were performed at baseline, with clinical and biochemical evaluations, 4‐extremity somatosensory evoked potentials, 12 min walk test and MRI studies of the CNS. Changes on these parameters were evaluated after 4 IT infusions of laronidase administered monthly via lumbar puncture. To our knowledge, this was the first MPS patient who received IT ERT. No major adverse events were observed. There were no clinically significant changes in serum chemistries. CSF GAG results revealed pretreatment values slightly above normal standards: 13.3 mg/L (NV < 12 mg/L) which after IT laronidase infusions were within normal levels (10.3 mg/L). 12MWT presented a 14% improvement, with better performance on stability and gait control. Maximum voluntary ventilation showed 55.6% improvement considering the percentage of predicted (26.7% at baseline compared to 41.9%); Maximum Inspiration Pressure improved 36.6% of predicted (26.8% at baseline to 36.7%); Pulmonary diffusion improved 17.6% of predicted %. In conclusion, although the improvement observed in this case with IT laronidase should be confirmed in further patients, this procedure seems to be a safe treatment for SCC in MPS I.

CNS involvement in Fabry disease: Clinical and imaging studies before and after 12 months of enzyme replacement therapy

Summary: We report the clinical and radiological central nervous system (CNS) findings of 8 Fabry disease patients, before (8/8) and after (7/8) 12 months of enzyme replacement therapy (ERT) with agalsidase-alpha. Eight biochemically proven Fabry disease patients (from four families) were included. Patients were evaluated at baseline and at regular intervals during 12 months of ERT. Evaluations included a thorough, standardized neurological examination, and magnetic resonance imaging (MRI) and angiography (MRA). Brain proton magnetic resonance spectroscopy (MRS) was also performed in 5/8 patients. The presence and location of grey- and white-matter lesions, the presence of vascular occlusion or ectasia on MRA and the metabolite ratios on MRS were determined, as well as their relation to age, symptoms and neurological examination. Neurological examination showed few abnormalities in these patients: scores varied (on a 0–100 scale) from zero to 5, at baseline and in the 12th month of ERT. The most consistent findings on MRI were asymmetric, widespread patterns of deep white-matter (WM) lesions, hyperintense on T2 and FLAIR-weighted images, found in 4/8 patients at baseline, predominantly in frontal and parietal lobes. These lesions did not correlate with other clinical variables, although there was a trend towards an association of the lesions with age and hearing loss. The youngest patient with MRI lesions was 24 years old. After 12 months of ERT, MRI was normal in 3/7, showed the same WM lesions in 2/7, and showed worsening of WM lesions in 2/7 patients (from the same family). Abnormal MRS metabolite ratios were detected at baseline in 4/5 patients. While neurological examination remained almost normal during the 12 months of ERT, new small-vessel CNS involvement still appeared in 2/7 patients. We do not know why ERT was not able to prevent this in these two related male patients. This could be due either to their older ages (46 and 36 years), or to a more pathogenic mutation. We conclude that MRI was more sensitive than neurological examination in detecting CNS involvement and progression in Fabry disease in the time interval studied.

White matter lesions in Fabry disease before and after enzyme replacement therapy: a 2-year follow-up

PURPOSE To report the clinical and neuroimaging, central nervous system (CNS) findings of patients with Fabry disease (FD) during 24 months of enzyme replacement therapy (ERT) with agalsidase-alpha. METHOD Eight patients were included. Six completed 24 months of ERT. Clinical and magnetic resonance imaging (MRI) data were obtained at 0, 12 and 24 months of ERT. White matter lesions (WML) were evaluated as well as their relation to age, symptoms and neurological examination (CNS score). RESULTS MRI was stable in 3 patients. WML and CNS score worsened in one patient, fluctuated in another, and improved in the sixth patient. In the whole series, there were 15 WML at baseline, and 19 at the 24th month. In two years, 4 lesions disappeared, whereas 8 appeared. CONCLUSION A widespread pattern of silent WML in FD was seen. In two years, some WML appeared, and some disappeared. If these phenomena were related to the natural history, remains to be demonstrated.

Body mass index is inversely correlated with the expanded CAG repeat length in SCA3/MJD patients.

Spinocerebellar ataxia type 3, also known as Machado–Joseph disease (SCA3/MJD), is an autosomal dominant neurodegenerative disorder with no current treatment. We aimed to evaluate the body mass index (BMI) of patients with SCA3/MJD and to assess the correlations with clinical, molecular, biochemical, and neuroimaging findings. A case–control study with 46 SCA3/MJD patients and 42 healthy, non-related control individuals with similar age and sex was performed. Clinical evaluation was done with the ataxia scales SARA and NESSCA. Serum insulin, insulin-like growth factor 1 (IGF-1) and magnetic resonance imaging normalized volumetries of cerebellum and brain stem were also assessed. BMI was lower in SCA3/MJD patients when compared to controls (p = 0.01). BMI was associated with NESSCA, expanded CAG repeat number (CAG)n, age of onset, age, disease duration, and serum insulin levels; however, in the linear regression model, (CAG)n was the only variable independently associated with BMI, in an inverse manner (R = −0.396, p = 0.015). In this report, we present evidence that low BMI is not only present in SCA3/MJD, but is also directly related to the length of the expanded CAG repeats, which is the causative mutation of the disease. This association points that weight loss might be a primary disturbance of SCA3/MJD, although further detailed analyses are necessary for a better understanding of the nutritional deficit and its role in the pathophysiology of SCA3/MJD.

Guidelines for acute ischemic stroke treatment - Part I

Executive Committee: Charles André, Aroldo Luiz Bacellar, Daniel da Cruz Bezerra, Roberto Campos, João José Freitas de Carvalho, Gabriel Rodrigues de Freitas, Roberto de Magalhães Carneiro de Oliveira, Sebastião Eurico Melo de Souza, Soraia Ramos Cabette Fábio, Eli Faria Evaristo, Jefferson Gomes Fernandes, Maurício Friedrich, Marcia Maiumi Fukujima, Rubens José Gagliardi, Sérgio Roberto Haussen, Maria Clinete Sampaio Lacativa, Bernardo Liberato, Alexandre L. Longo, Sheila Cristina Ouriques Martins, Ayrton Roberto Massaro, Cesar Minelli, Carla Heloísa Cabral Moro, Jorge El-Kadum Noujaim, Edison Matos Nóvak, Jamary Oliveira-Filho, Octávio Marques Pontes-Neto, César Noronha Raffin, Bruno Castelo Branco Rodrigues, José Ibiapina Siqueira-Neto, Elza Dias Tosta, Raul Valiente, Leonardo Vedolim, Marcelo Gabriel Veja, Leonardo Vedolin, Fábio Iuji Yamamoto, Viviane Flumignan Zétola. Correspondence: Jamary Oliveira-Filho; Rua Reitor Miguel Calmon s/n; Instituto de Ciências da Saúde / sala 455; 40110-100 Salvador BA Brasil; E-mail: jamaryof@ufba.br Conflict of interest: There is no conflict of interest to declare. Received 18 February 2012; Received in final form 22 February 2012; Accepted 29 February 2012 Guidelines for acute ischemic stroke treatment – Part I

Magnetic resonance imaging findings in Hunter syndrome

Hunter syndrome is a rare genetic lysosomal storage disease that is caused by a deficiency, or absence, of iduronate‐2‐sulphatase, an enzyme needed to break down specific glycosaminoglycans (GAGs). As a result, GAGs build up in various tissues throughout the body leading to adverse neurological and non‐neurological effects. This literature review focuses on the neurological findings. Although few magnetic resonance imaging studies have been conducted, those done have shown that patients with Hunter syndrome generally exhibit brain atrophy, enlarged periventricular spaces and ventriculomegaly. Similar findings have been reported in other mucopolysaccharide disorders. Enzyme replacement therapy is a novel treatment which has had success in treating peripheral disease in mice and humans.

X-linked adrenoleukodystrophy: clinical course and minimal incidence in South Brazil.

UNLABELLED X-linked adenoleukodystrophy is a genetic disease that affects the degradation of very long-chain fatty acids. In male patients, common pictures are the cerebral form (CALD), myeloneuropathy (AMN), and Addison-only. OBJECTIVE To describe the clinical course of affected male patients from South Brazil between 1993 and 2007. METHODS Affected male patients and their maternal lineages were studied from a clinical, neurological and biochemical standpoint. RESULTS Eighty-three male patients from 30 families were biochemically evaluated: 51 were affected. 27/51 (54%) presented the cerebral form; 11/51 had AMN (22%); 5 had Addison-only (10%), and 8 (16%) were asymptomatic. Between 2002 and 2006, the minimal incidence was 1:35,000 males in our State (South Brazil). Forty-three affected individuals were followed for 5.4+/-3.7 years. Of 10 boys detected at early stages, three developed CALD. These three boys and another five CALD at baseline were referred to hematopoietic stem cell transplantation. Seven transplants were carried out, 5 with good clinical evolution after 2.2 years post-transplant. The non-transplanted case was later defined as a stable cerebral form. DISCUSSION Among the present families, the observed cases were comparable to the 50% expected by Mendelian segregation. Based on the natural history, the number of cases that developed CALD was similar to the expected. Transplants were successful in 70% of cases. The occurrence of a stable cerebral form pointed to an urgent need for better markers of active cerebral disease.

Serum insulin-like system alterations in patients with spinocerebellar ataxia type 3.

Spinocerebellar ataxias (SCAs) constitute a group of autosomal dominant neurodegenerative disorders with no current treatment. The insulin/insulin‐like growth factor 1 (IGF‐1) system (IIS) has been shown to play a role in the neurological dysfunction of SCAs and other polyglutamine disorders. We aimed to study the biomarker profile of serum IIS components in SCA3. We performed a case–control study with 46 SCA3 patients and 42 healthy individuals evaluating the peripheral IIS profile (insulin, IGF‐1, IGFBP1 and 3) and the correlation with clinical, molecular, and neuroimaging findings. SCA3 patients presented lower insulin and IGFBP3 levels and higher insulin sensitivity (HOMA2), free IGF‐I, and IGFBP1 levels when compared with controls. IGFBP‐1 levels were directly associated with CAG expanded repeat length; IGF‐1 was associated with the volumetries of specific brainstem regions on magnetic resonance imaging (MRI). Insulin levels and sensitivity were related to age at onset of symptoms. Our findings indicate an involvement of IIS components in SCA3 neurobiology and IGFBP‐1 as a potential biomarker of the disease.

Depressive Mood is Associated with Ataxic and Non-Ataxic Neurological Dysfunction in SCA3 Patients

We read with interest the article recently published in Cerebellum by Klinke et al., entitled “Neuropsychological features of patients with spinocerebellar ataxia (SCA) types 1, 2, 3, and 6,” particularly because it pertains to the depressive mood scores obtained in those patients [1]. SCAs are a group of autosomal dominant ataxic disorders affecting mainly the cerebellum and its afferent and efferent connections; however, in most SCAs the consecutive degenerative process also involves extracerebellar structures [2]. A recent survey of subjective health status performed in 526 SCA patients from the European Integrated Project on Spinocerebellar Ataxias (EUROSCA) clinical group, found that 46% of those patients reported depression/anxiety problems, which was one of the three independent predictors of subjective health status together with ataxia severity and extent of noncerebellar involvement [3]. We previously reported that SCA3 symptomatic patients have higher depressive mood scores on the Beck Depression Inventory (BDI) than controls (caregivers), whereas their children at risk have BDI scores lower than the same control group. Depressive mood scores on the BDI correlated with the neurological disability measured by the Barthel Index of Physical Incapacitation in our study [4], and correlated with the dominant motor hand dysfunction in the study of Klinke et al. [1]. In order to further evaluate depressive symptoms in SCA3 patients and their relationship with the recently obtained ataxia scores, we performed a case–control study in 49 molecularly confirmed SCA3 patients from the neurogenetics clinic of Hospital de Clínicas de Porto Alegre (HCPA), and 41 healthy, nonrelated individuals with similar age, gender, and environmental characteristics—such as spouses or neighbors of the affected individuals (mainly caregivers)—as the control group. The ATXN3 expanded regions were analyzed as previously described [5]. The BDI, in its Brazilian version [6], was applied to quantify the depressive symptoms of subjects. BDI is usually interpreted as follows: 0–10 (absence or subtle depression), 11–18 (mild depression), 19–29 (moderate depression), and 30–63 (severe depression). Two clinical ataxia scales were applied: the Scale for the Assessment and Rating of Ataxia (SARA) [7], which evaluates ataxic signals, and the Neurological Examination Score for Spinocerebellar Ataxia (NESSCA) [8], which is a global neurological evaluation encompassing ataxic and nonataxic signals. Both scores vary from 0–40 points, increasing with disease severity. Data on disease duration and age of onset were provided by patients and their relatives. For detailed patient characteristics, see Table 1. SCA3 patients presented higher depressive scores on BDI (p= J. A. M. Saute : L. B. Jardim Postgraduate Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

Topiramate is effective for status epilepticus and seizure control in neuraminidase deficiency

Sialidosis, a rare lysosomal storage disorder is caused by a deficiency of the enzyme α-N-acetyl neuraminidase, resulting from mutations in the NEU1 gene. Its main phenotypes are Sialidosis types I (milder form) and II (earlier onset). Sialidosis type II is characterized by developmental delay, macular cherry-red spot, visceromegaly, coarse facies, dysostosis multiplex, and myoclonus. We report a case of status epilepticus (SE) in a patient with Sialidosis type II which had good response to topiramate.