Sabrina Ravaglia

Postinfectious inflammatory disorders Subgroups based on prospective follow-up

Background: Acute disseminated encephalomyelitis (ADEM) refers to a monophasic acute multifocal inflammatory CNS disease. However, both relapsing and site-restricted variants, possibly associated with peripheral nervous system (PNS) involvement, are also observed, and a systematic classification is lacking. Objective: To describe a cohort of postinfectious ADEM patients, to propose a classification based on clinical and instrumental features, and to identify subgroups of patients with different prognostic factors. Methods: Inpatients of a Neurologic and Infectious Disease Clinic affected by postinfectious CNS syndrome consecutively admitted over 5 years were studied. Results: Of 75 patients enrolled, 60 fulfilled criteria for ADEM after follow-up lasting from 24 months to 7 years. Based on lesion distribution, patients were classified as encephalitis (20%), myelitis (23.3%), encephalomyelitis (13.3%), encephalomyeloradiculoneuritis (26.7%), and myeloradiculoneuritis (16.7%). Thirty patients (50%) had a favorable outcome. Fifteen patients (25%) showed a relapsing course. Poor outcome was related with older age at onset, female gender, elevated CSF proteins, and spinal cord and PNS involvement. All but two patients received high-dose steroids as first-line treatment, with a positive response in 39 (67%). Ten of 19 nonresponders (53%) benefited from high-dose IV immunoglobulin; 9 of 10 had PNS involvement. The data were not controlled. Conclusions: A high prevalence of “atypical variants” was found in this series, with site-restricted damage or additional peripheral nervous system (PNS) involvement. Prognosis and response to steroids were generally good, except for some patient subgroups. In patients with PNS involvement and steroid failure, a favorable effect of IV immunoglobulin was observed.

Diagnosis of glycogenosis type II

The diagnosis of glycogenosis type II is often complicated by the rarity of the condition and the heterogeneity of the clinical manifestations of the disease. It is a progressive, debilitating, and often fatal neuromuscular disorder that manifests as a continuum of clinical phenotypes, which vary with respect to organ involvement, age at onset, and severity. Early diagnosis requires both increased awareness among physicians regarding the clinical characteristics of the disease and fast and reliable acid alpha-glucosidase (GAA) enzyme activity assays to confirm the GAA deficiency. The clinical diagnosis of glycogenosis type II is confirmed by virtual absence (found in infants) and marked reduced activity (found in juveniles and adults) of GAA enzyme in blood samples, cultured fibroblasts, and muscle biopsies. This article specifically highlights the need for early recognition of the clinical manifestation of the disease in infants, juveniles, and adults. Descriptions of the main clinical features of the condition, as well as differential diagnosis are included. In addition, the tests required for a confirmed diagnosis are described, and use of muscle imaging to evaluate muscle pathology is reviewed.

Immune-mediated neuropathies in myeloma patients treated with bortezomib.

OBJECTIVE Bortezomib is a new chemotherapeutic drug available for the treatment of lymphoid disorders, including multiple myeloma. Although its primary mechanism of action is proteasome inhibition, other mechanisms can contribute to the therapeutic effects, including modulation of inflammatory cytokines and immune response. One of the main toxic effects of bortezomib is peripheral neuropathy, usually occurring in the form of a painful, sensory axonal neuropathy. The mechanisms of peripheral damage, however, are still unclear. We here report a series of patients treated with bortezomib, who developed a peripheral damage possibly related to immuno-mediated, rather than toxic, mechanisms. METHODS Five patients who developed a peripheral neuropathy with severe motor involvement under bortezomib treatment underwent CSF, electrophysiological, and spinal cord MRI examinations. RESULTS Peripheral damage was characterized by: demyelinating or mixed axonal-demyelinating neuropathy, with prominent motor involvement; albumin-cytological dissociation; lumbar root enhancement on MRI in 2/5 patients; favourable outcome in 4/5 patients after immune treatments, either steroids (2 patients) or IVIg (2 patients). CONCLUSIONS In some instances, the peripheral damage associated with bortezomib may recognize immuno-mediated mechanisms. SIGNIFICANCE This form of bortezomib-associated neuropathy needs to be recognized as treatable condition, as it may respond to immune therapies. Unexplained worsening of neurological dysfunction despite bortezomib discontinuation, with prominent motor involvement and CSF signs of inflammation, may be the clues to this complication.

Muscle MRI in adult-onset acid maltase deficiency

We report the spectrum of muscle involvement on magnetic resonance imaging in 11 patients with a molecularly confirmed diagnosis of adult-onset acid maltase deficiency at different clinical stages. Muscle magnetic resonance imaging showed a selective progressive pattern of muscle involvement with a constant involvement of the adductor magnus and semimembranosus at the early stage of the disease and a later fatty infiltration of the long head of the biceps femoris, semitendinosus and of the anterior thigh muscles. In the advanced phases a selective sparing of sartorius, rectus, and gracilis muscles and peripheral portions of the vastus lateralis was also evident. Muscle strength and magnetic resonance imaging findings were positively correlated. The results suggest that muscle magnetic resonance imaging may provide valuable diagnostic guidance for the assessment of accurate selective muscular involvement in acid maltase deficiency and may help monitor the progression of the disorder. Further control studies in a larger cohort are needed to evaluate the specificity of these findings.

Management and treatment of glycogenosis type II

Glycogenosis type II is a multisystem disorder that requires management by a multidisciplinary team. The team should include several specialists, such as a metabolic disease specialist or biochemical geneticist, cardiologist, pulmonologist, neurologist, neuromuscular specialist, intensivist, orthopedist, respiratory therapist, physical therapist, occupational therapist, otolaryngologist speech therapist, audiologist, genetic counselor, and a metabolic dietician, who, as a team, will be capable of addressing the different manifestations of the condition. Aspects of functional assessment, rehabilitation, nutritional management, care coordination, nursing, genetic counseling, prenatal diagnosis, and screening are discussed in this article. In addition, treatment of glycogenosis type II is reviewed with attention to emerging therapeutic options.

Cytokines and chemokines in cerebrospinal fluid and serum of adult patients with acute disseminated encephalomyelitis.

Cytokines and chemokines contribute to the pathogenesis of acute disseminated encephalomyelitis (ADEM). Using a multiplex immunochemiluminescence ELISA, we measured 8 Th1/Th2 cytokines and 18 chemokines in the cerebrospinal fluid (CSF) and serum of 17 ADEM patients, 14 multiple sclerosis (MS) patients, and 7 healthy controls (HCs). Relative to HCs, ADEM patients had significantly high mean CSF concentrations of chemokines with attractant/activating properties towards neutrophils (CXCL1 and CXCL7), monocytes/T cells (CCL3 and CCL5), Th1 cells (CXCL10), and Th2 cells (CCL1, CCL22, and CCL17). Mean CSF concentrations of CXCL7, CCL1, CCL22, and CCL17 were higher in ADEM than in MS, whereas those of CCL11 were lower in MS than in ADEM and HCs. CSF pleocytosis correlated with CSF concentrations of CXCL1, CXCL10, CCL1, CCL17, and CCL22. Most of the functionally homologous chemokines correlated with each other. CSF Th1/Th2 cytokines were not detectable in most samples. Their mean concentrations did not differ in the three groups, and the same held for serum cytokines and chemokines. Our data suggest that the upregulation of chemokines active on neutrophils and Th2 cells differentiates ADEM from MS inflammation, and that both Th1 and Th2 chemokines might be produced in ADEM. Chemokines upregulated in ADEM could become CSF biomarkers after a posteriori evaluations in unselected case series.

Severe steroid-resistant post-infectious encephalomyelitis: General features and effects of IVIg

Based on their presumed immuno-mediated etiology, post-infectious CNS disorders are commonly treated with high-dose steroids. Factors influencing treatment effectiveness, possible alternative options for steroid-resistant cases, and their outcome profiles, remain unclear. We here describe the clinical features, the prognosis and the efficacy of i. v. immunoglobulins (IVIg) in a series of severe ADEM refractory to steroids. We performed an inception cohort study on inpatients of the Neurologic and Infectious Disease Clinics, consecutively admitted over eight years, with a minimum two-year follow-up. Nineteen patients affected by classic and site-restricted ADEM were treated with IVIg after steroid failure. Five other patients received IVIg as first-line treatment due to steroids contraindications: although not included in the analysis, they were monitored for anecdotal comparison. Steroids were administered as IV 6-methylprednisolone (6-MP) 500/1000 mg daily until a maximum dose of 6–8 g; IVIg were administered at 0.4 g/kg/day for 5 days. The outcome was assessed by the Scripps Neurological Rating Scale (SNRS) score with determined periodicity. We observed that steroid-resistant patients showed high prevalence of PNS damage (89%) and myelitis (95 %). Other features were old age, severe disability at onset, and moderate to severe blood-brain-barrier (BBB) damage on CSF. In 10/19 patients (53 %) IVIg were effective, the clinical improvement beginning within the end of the five-day cycle,without relapses. Prominent effects of IVIg were detectable on motor dysfunction. Milder onset disability (p = 0.013) and lower CSF albumin (p = 0.006) were the predictors of IVIg response.Among steroid-free patients, 3/5 were responsive to IVIg. We conclude that IVIg can be useful in a portion of patients with severe steroid-resistant ADEM and prominent motor dysfunction. Unsolved issues regard the usefulness of IVIg in less selected groups, and the spectrum of their clinical effects.

Spinocerebellar ataxia type 17 (SCA17): Oculomotor phenotype and clinical characterization of 15 Italian patients

SCA17 is a rare type of autosomal dominant spinocerebellar ataxia caused by a CAG/CAA expansion in the gene encoding the TATA-binding protein (TBP).We screened for triplet expansion in the TBP gene 110 subjects with progressive cerebellar ataxia and 94 subjects with Huntington-like phenotype negative at specific molecular tests. SCA17 mutation-positive subjects were found in both groups of patients. Expanded alleles with ≥ 44 CAG/CAA repeats were identified in 11 individuals and in 4 non-symptomatic relatives. Eleven de novo diagnosed patients and four patients previously reported underwent extensive clinical, neuroradiological and oculographic examination. Cerebellar signs and symptoms were present in all cases; 80% of the patients had mild to severe cognitive deficits; 66% of patients showed choreic movements; pyramidal signs, bradykinesia and dystonia were observed in approx 50% of the cases. MRI demonstrated cortical and cerebellar atrophy in all patients, whereas neurophysiological examination excluded signs of peripheral nervous system involvement. Oculographic examinations were performed in 9 out of 15 patients and showed a distinct pattern of oculomotor abnormalities, characterized by impairment of smooth pursuit, defects in the saccade accuracy, normal saccade velocity, hyperreflexia of vestibuloocular reflexes, and absence of nystagmus.In summary, this study presents one of the largest series of SCA17 patients in Europe. In our group of patients, SCA17 represents the third most frequent SCA genotype. Our clinical data confirm the large variability in SCA17 phenotypic presentation, and indicate that a peculiar combination of neuroradiological, electrophysiological and oculomotor findings is recognizable in SCA17.

A chaperone enhances blood α-glucosidase activity in Pompe disease patients treated with enzyme replacement therapy.

Enzyme replacement therapy is currently the only approved treatment for Pompe disease, due to acid α-glucosidase deficiency. Clinical efficacy of this approach is variable, and more effective therapies are needed. We showed in preclinical studies that chaperones stabilize the recombinant enzyme used for enzyme replacement therapy. Here, we evaluated the effects of a combination of enzyme therapy and a chaperone on α-glucosidase activity in Pompe disease patients. α-Glucosidase activity was analyzed by tandem-mass spectrometry in dried blood spots from patients treated with enzyme replacement therapy, either alone or in combination with the chaperone N-butyldeoxynojirimycin given at the time of the enzyme infusion. Thirteen patients with different presentations (3 infantile-onset, 10 late-onset) were enrolled. In 11 patients, the combination treatment resulted in α-glucosidase activities greater than 1.85-fold the activities with enzyme replacement therapy alone. In the whole patient population, α-glucosidase activity was significantly increased at 12 hours (2.19-fold, P = 0.002), 24 hours (6.07-fold, P = 0.001), and 36 hours (3.95-fold, P = 0.003). The areas under the curve were also significantly increased (6.78-fold, P = 0.002). These results suggest improved stability of recombinant α-glucosidase in blood in the presence of the chaperone.

Postinfectious neurologic syndromes A prospective cohort study

Objectives: Postinfectious neurologic syndromes (PINSs) of the CNS include heterogeneous disorders, sometimes relapsing. In this study, we aimed to a) describe the spectrum of PINSs; b) define predictors of outcome in PINSs; and c) assess the clinical/paraclinical features that help differentiate PINSs from multiple sclerosis (MS). Methods: In this prospective cohort study, adult inpatients with PINSs underwent extensive diagnostic assessment and therapeutic protocols at inclusion and during a minimum 2-year follow-up. We compared them with newly diagnosed, treatment-naive patients with MS, also prospectively recruited. Results: The study sample comprised 176 patients with PINSs aged 59.9 ± 17.25 years (range: 18–80 years) divided into 2 groups: group 1 (CNS syndromes, 64%)—encephalitis, encephalomyelitis, or myelitis; and group 2 (CNS + peripheral nervous system [PNS] syndromes, 36%)—encephalomyeloradiculoneuritis or myeloradiculoneuritis. We observed the patients for 24 to 170 months (median 69 months). Relapses, almost invariably involving the spinal cord, occurred in 30.5%. PNS involvement was an independent risk factor for relapses (hazard ratio 2.8). The outcome was poor in 43% of patients; risk factors included older age, greater neurologic disability at onset, higher serum-CSF albumin percentage transfer, myelitis, and PNS involvement. Steroid resistance occurred in 30% of the patients, half of whom responded favorably to IV immunoglobulins. Compared with MS, PINSs were characterized by older age, lower tendency to relapse, and distinct CSF findings. Conclusions: The category of PINSs should be revised: most of the clinical variants have a poor prognosis and are not readily classifiable on the basis of current knowledge. PNS involvement has a critical role in relapses, which seem to affect the spine only.