Central Neurological Involvement Research Articles

Cluster Analysis to Explore Clinical Subphenotypes of Eosinophilic Granulomatosis With Polyangiitis.

Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results. The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.

Cluster Analysis To Explore Clinical Subphenotypes Of Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss).

Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA) could be determined by presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal, mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central or peripheral neurological involvement); a second model also included ANCA results. The analyses included 489 patients diagnosed in 1984-2015. ANCA were detected in 37.2% of patients, mostly P-ANCA (85.4%) and/or anti-myeloperoxidase (87.0%). Compared with ANCA-negative patients, those with ANCA had more renal (P<0.001) and peripheral neurological involvement (P=0.04), fewer cardiovascular signs (P<0.001) and fewer biopsies with eosinophilic tissue infiltrates (P=0.001). The cluster analyses generated four (model without ANCA) and five clusters (model with ANCA). Both models identified three identical clusters of 34, 39 and 40 patients according to the presence or absence of ENT, CNS and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.

Efficacy of intravenous immunoglobulin (IVIg) on COVID-19-related neurological disorders over the last 2 years: an up-to-date narrative review.

Among the clinical manifestations of SARS-CoV-2 infection, neurological features have been commonly reported and the state-of-the-art technique suggests several mechanisms of action providing a pathophysiological rationale for central and peripheral neurological system involvement. However, during the 1st months of the pandemic, clinicians were challenged to find the best therapeutic options to treat COVID-19-related neurological conditions. We explored the indexed medical literature in order to answer the question of whether IVIg could be included as a valid weapon in the therapeutic arsenal against COVID-19-induced neurological disorders. Virtually, all reviewed studies were in agreement of detecting an acceptable to great efficacy upon IVIg employment in neurological diseases, with no or mild adverse effects. In the first part of this narrative review, the interaction of SARS-CoV-2 with the nervous system has been discussed and the IVIg mechanisms of action were reviewed. In the second part, we collected scientific literature data over the last 2 years to discuss the use of IVIg therapy in different neuro-COVID conditions, thus providing a summary of the treatment strategies and key findings. Intravenous immunoglobulin (IVIg) therapy is a versatile tool with multiple molecular targets and mechanisms of action that might respond to some of the suggested effects of infection through inflammatory and autoimmune responses. As such, IVIg therapy has been used in several COVID-19-related neurological diseases, including polyneuropathies, encephalitis, and status epilepticus, and results have often shown improvement of symptoms, thus suggesting IVIg treatment to be safe and effective.

Autoimmune neuromyotonia.

Autoimmune neuromyotonia encompasses a group of rare immune-mediated neurological disorders frequently associated with anti-contactin-associated protein-like 2 (CASPR2) antibodies and featuring clinical and electrical signs of peripheral nerve hyperexcitability (PNH). We aim to summarize the current knowledge on immune-mediated neuromyotonia, focusing on clinical presentations, pathophysiology, and management. Neuromyotonia is a major feature of several autoimmune neurological syndromes characterized by PNH with or without central neurological system involvement. Experimental and clinical evidence suggest that anti-CASPR2 antibodies are directly pathogenic in autoimmune neuromyotonia patients. Neuromyotonia, a form of PNH, is a major feature in several syndromes associated with anti-CASPR2 antibodies, including cramp-fasciculation syndrome, Isaacs syndrome, Morvan syndrome, and autoimmune limbic encephalitis. Diagnosis relies on the identification of motor, sensory, and autonomic signs of PNH along with other neurological symptoms, anti-CASPR2 antibody-positivity, and of characteristic electroneuromyographic abnormalities. Paraneoplastic associations with thymoma are possible, especially in Morvan syndrome. Patients usually respond to immune-active treatments, including steroids, intravenous immunoglobulins, plasma exchanges, and rituximab.

Isolated CNS Sarcoidosis Versus Systemic Sarcoidosis With CNS Involvement: A Same Disease?

To describe patients with definite isolated central neurosarcoidosis. To compare their characteristics to a group of systemic sarcoidosis with central neurologic involvement. Monocentric retrospective study of all patients presenting with central neurosarcoidosis (NS) over a 10 year period, subsequently divided into 2 groups: isolated neurosarcoidosis (INS) and systemic neurosarcoidosis (SNS). We report 10 cases of INS and subsequently, we compared their characteristics to a group of 30 patients with SNS. INS patients exhibited brain parenchymal involvement (8/10), meningeal disease (8/10), myelitis (3/10), cranial neuropathy (3/10), neuroendocrine impairment (1/10). Cerebro-spinal fluid (CSF) analysis was conducted in 8/10 patients and showed pleocytosis in 6/8 (75%), elevated protein level in (4/8) 50%, oligoclonal intrathecal synthesis in 1/5 (20%). All patients received steroids, 7/10 (70%) required associated immunosuppressive therapy, 5 of which TNFα inhibitors. When compared to patients with SNS, INS patients were more likely to experience seizures (60% vs 23.3%); display encephalic parenchymal enhancing lesions (80% vs 39.3%) or encephalic leptomeningeal involvement (80% vs 35.7%). Serum angiotensin converting enzyme (ACE) was elevated in a third of patients with SNS but none of those with INS. The phenotypes of patients with INS are similar to the ones described in SNS. Serum ACE should not be regarded as a diagnostic test in patients with isolated neurosarcoidosis but could be useful in detecting subclinical extra neurologic involvement during follow up.

Argonaute Autoantibodies as Biomarkers in Autoimmune Neurologic Diseases.

ObjectiveTo identify and characterize autoantibodies (Abs) as novel biomarkers for an autoimmune context in patients with central and peripheral neurologic diseases.MethodsTwo distinct approaches (immunoprecipitation/mass spectrometry–based proteomics and protein microarrays) and patients' sera and CSF were used. The specificity of the identified target was confirmed by cell-based assay (CBA) in 856 control samples.ResultsUsing the 2 methods as well as sera and CSF of patients with central and peripheral neurologic involvement, we identified Abs against the family of Argonaute proteins (mainly AGO1 and AGO2), which were already reported in systemic autoimmunity. AGO-Abs were mostly of immunoglobulin G 1 subclass and conformation dependent. Using CBA, AGO-Abs were detected in 21 patients with a high suspicion of autoimmune neurologic diseases (71.4% were women; median age 57 years) and only in 4/856 (0.5%) controls analyzed by CBA (1 diagnosed with small-cell lung cancer and the other 3 with Sjögren syndrome). Among the 21 neurologic patients identified, the main clinical presentations were sensory neuronopathy (8/21, 38.1%) and limbic encephalitis (6/21, 28.6%). Fourteen patients (66.7%) had autoimmune comorbidities and/or co-occurring Abs, whereas AGO-Abs were the only autoimmune biomarker for the remaining 7/21 (33.3%). Thirteen (61.9%) patients were treated with immunotherapy; 8/13 (61.5%) improved, and 3/13 (23.1%) remained stable, suggesting an efficacy of these treatments.ConclusionsAGO-Abs might be potential biomarkers of autoimmunity in patients with central and peripheral nonparaneoplastic neurologic diseases. In 7 patients, AGO-Abs were the only biomarkers; thus, their identification may be useful to suspect the autoimmune character of the neurologic disorder.Classification of EvidenceThis study provides Class III evidence that AGO-Abs are more frequent in patients with autoimmune neurologic diseases than controls.

Central and peripheral nervous system involvement by COVID-19: a systematic review of the pathophysiology, clinical manifestations, neuropathology, neuroimaging, electrophysiology, and cerebrospinal fluid findings

BackgroundSARS-CoV-2 can affect the human brain and other neurological structures. An increasing number of publications report neurological manifestations in patients with COVID-19. However, no studies have comprehensively reviewed the clinical and paraclinical characteristics of the central and peripheral nervous system’s involvement in these patients. This study aimed to describe the features of the central and peripheral nervous system involvement by COVID-19 in terms of pathophysiology, clinical manifestations, neuropathology, neuroimaging, electrophysiology, and cerebrospinal fluid findings.MethodsWe conducted a comprehensive systematic review of all the original studies reporting patients with neurological involvement by COVID-19, from December 2019 to June 2020, without language restriction. We excluded studies with animal subjects, studies not related to the nervous system, and opinion articles. Data analysis combined descriptive measures, frequency measures, central tendency measures, and dispersion measures for all studies reporting neurological conditions and abnormal ancillary tests in patients with confirmed COVID-19.ResultsA total of 143 observational and descriptive studies reported central and peripheral nervous system involvement by COVID-19 in 10,723 patients. Fifty-one studies described pathophysiologic mechanisms of neurological involvement by COVID-19, 119 focused on clinical manifestations, 4 described neuropathology findings, 62 described neuroimaging findings, 28 electrophysiology findings, and 60 studies reported cerebrospinal fluid results. The reviewed studies reflect a significant prevalence of the nervous system’s involvement in patients with COVID-19, ranging from 22.5 to 36.4% among different studies, without mortality rates explicitly associated with neurological involvement by SARS-CoV-2. We thoroughly describe the clinical and paraclinical characteristics of neurological involvement in these patients.ConclusionsOur evidence synthesis led to a categorical analysis of the central and peripheral neurological involvement by COVID-19 and provided a comprehensive explanation of the reported pathophysiological mechanisms by which SARS-CoV-2 infection may cause neurological impairment. International collaborative efforts and exhaustive neurological registries will enhance the translational knowledge of COVID-19’s central and peripheral neurological involvement and generate therapeutic decision-making strategies.RegistrationThis review was registered in PROSPERO 2020 CRD42020193140 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020193140

Neurologic Features Associated With SARS-CoV-2 Infection in Children: A Case Series Report.

Although multiple neurologic manifestations associated with SARS-CoV-2 infection have been described in adults, there is little information about those presented in children. Here, we described neurologic manifestations associated with COVID-19 in the pediatric population. Retrospective case series report. We included patients younger than 18 years, admitted with confirmed SARS-CoV-2 infection and neurologic manifestations at our hospital in Santiago, Chile. Demographics, clinical presentations, laboratory results, radiologic and neurophysiological studies, treatment, and outcome features were described. Cases were described based on whether they presented with predominantly central or peripheral neurologic involvement. Thirteen of 90 (14.4%) patients admitted with confirmed infection presented with new-onset neurologic symptoms and 4 patients showed epilepsy exacerbation. Neurologic manifestations ranged from mild (headache, muscle weakness, anosmia, ageusia), to severe (status epilepticus, Guillain-Barré syndrome, encephalopathy, demyelinating events). We found a wide range of neurologic manifestations in children with confirmed SARS-CoV-2 infection. In general, neurologic symptoms were resolved as the systemic presentation subsided. It is essential to recognize and report the main neurologic manifestations related to this new infectious disease in the pediatric population. More evidence is needed to establish the specific causality of nervous system involvement.

Cerebral Localization of Chronic Lymphocytic Leukemia Simulating Progressive Multifocal Leukoencephalopathy: The Lessons from a Case

Background: Central neurological involvement is the most frequent extra hematological manifestation of chronic lymphocytic leukemia; it is multifactorial and rarely due to a cerebral localization of the disease. We report a case of cerebral localization of chronic lymphoid leukemia whose clinical and radiological aspects were very suggestive of progressive multifocal leukoencephalopathy. Case Presentation: A 65-year-old patient who was HIV-negative (human immunodeficiency virus), had consulted for bilateral axillary, cervical and inguinal lymphadenopathy associated with major asthenia and hyper lymphocytosis (lymphocyte count was 11 giga/l). Chronic lymphocyticleukemia with TP53 mutation was diagnosed and treatment with Ibrutinib 420 mg/day was initiated. After 2 months of treatment, the evolution was marked by the onset of neurological disorders whose clinical-radiological presentation and temporal evolution had led to the diagnosis of progressive multifocal leukoencephalopathy. In the absence of virological evidence in the cerebrospinal fluid analysis, a stereotactic biopsy of the brain lesions had been performed, making it possible to formally rule out this infectious hypothesis and to demonstrate cerebral invasion by tumour cells. Immuno-chemotherapy combining Rituximab-Cyclophosphamide-Doxorubicin-Vincristine-Prednisone-Ibrutinib (RCHOP-Ibrutinib) with intrathecal chemotherapy resulted in a very good clinical-radiological response. Conclusion: The appearance of neurological manifestations in the context of chronic lymphocytic leukemia must systematically lead to a search for a cerebral localization of the disease. In the absence of virological evidence in the cerebrospinal fluid, any suspicion of progressive multifocal leukoencephalopathy in this context should lead to the histological study of brain lesions.

Peduncular Hallucinosis and Overlapping Antiganglioside Antibody Syndrome

Guillain Barre Syndrome (GBS), Miller Fisher Syndrome (MFS) and Bickerstaff Brainstem Encephalitis (BBE) form part of the same disease spectrum, sharing some clinical signs and auto-immune based mechanisms with antiganglioside antibodies. GBS, the most common cause of subacute flaccid paralysis, is a well-known and extensively described syndrome. MFS is characterized by subacute ophthalmoplegia, ataxia and areflexia. In 1957, Bickerstaff described some patients who, in addition to ataxia and ophthalmoplegia, had abnormal mental status, corresponding to brainstem involvment. Neurological manifestations associated with anti-GQ1b antibodies can occur in isolation or in association. We report the case of a woman with an unusual psychiatric presentation (peduncular hallucinosis) of anti-GQ1b antibody syndrome, with features of these three diseases, and a dramatic improvement with immunoglobulin therapy. Peduncular hallucinosis are a rare form of visual hallucination. They are often described as colourful visions of people and animals, and are usually associated with vascular lesions in the midbrain and thalamus. This provides further evidence of the broad spectrum of neurological diseases associated with antiganglioside antibodies. To the best of our knowledge this is the first description of PH complicating BBE. Clinicians should be aware of the existence of overlapping syndrome with combined central and peripherical neurological system involvement.

MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy.

MPV17 encodes a putative channel-forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis. MPV17 mutations were first reported in patients with Navajo neurohepatopathy, an autosomal recessive mitochondrial DNA depletion syndrome, characterized by early-onset liver failure, failure to thrive as well as central and peripheral neurological involvement. Recently, two patients with juvenile-onset peripheral sensorimotor neuropathy associated with an MVP17 c.122G>A (p.Arg41Gln) variant have been reported. Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants. Patients of the first family carried the known c.122G>A variant and affected individuals of the second family had a novel c.376-9T>G near-splice variant, which was shown to result in an in-frame deletion of 11 amino acids. This report provides further evidence that MPV17 mutations should be considered in patients with pure, non-syndromic axonal neuropathy.

Leukodystrophy with disorders of sex development due to WT1 mutations

BackgroundHypomyelinating leukodystrophies represent an expanding group of neurogenetic disorders characterized primarily by central nervous system hypomyelination and variable neurological and non-neurological involvement. Hypomyelinating disorders have been rarely associated with gonadal dysfunction, being mainly represented by hypogonadotrophic hypogonadism in 4H syndrome. WT1 gene-associated disorders are classically associated with complex phenotypes including early carcinogenic risk for gonadoblastoma and Wilms' tumor, chronic renal failure, nephrotic syndrome and sex developmental disorders in intersex disorders and ambiguous genitalia. MethodsThe authors describe three non-related Brazilian patients with hypomyelinating leukodystrophy associated with complex neurological and systemic dysfunction with WT1 gene mutations. ResultsAll described patients presented with similar neuroimaging features including thin corpus callosum, mild to moderate cerebellar atrophy and diffuse periventricular and profound hypomyelinating leukodystrophy involving supratentorial white matter with classical compromise linked to inherited non-somatic WT1 gene mutations in a similar pattern to Denys-Drash syndrome, including nephrotic syndrome with different glomerular disease, chronic renal failure, intersex disorder with ambiguous genitalia, and early occurrence of specific tumors, such as Wilms' tumor and gonadoblastoma. ConclusionsClinicians must include WT1 gene mutations in the differential diagnosis of hypomyelinating leukodystrophy with nephrotic syndrome, chronic renal failure, ambiguous genitalia or sex developmental disorders.

Gastroparesis may be the cause of unexplained dyspepsia in patients with primary Sjögren syndrome

Upper digestive symptoms may be present in up to 50% of patients with primary Sjögren syndrome (pSS). We report a retrospective cohort of gastroparesis in a population of pSS presenting unexplained dyspepsia. Delayed gastric emptying was defined by a gastric emptying time above 113min or by a retention percentage at 4h more than 10% on scintigraphy. Eleven patients with primary Sjögren syndrome and gastroparesis were included in a retrospective study. Every patients were women of age 48±18y. The average time of gastric emptying was 725,18±704,45min. 64% of patients had abdominal pain or gastric heaviness. A central or peripheral neurologic involvement was described in respectively 9 and 27% of cases. The diagnostic delay of gastroparesis was higher than 24 months. In primary Sjögren syndrome, gastroparesis should be suspected in case of unexplained dyspepsia, and a scintigraphy performed to prove the diagnosis. A neurologic involvement could explain gastroparesis, but prospective studies are needed for a better understanding of this disorder.

Revisiting mitochondrial ocular myopathies: a study from the Italian Network.

Ocular myopathy, typically manifesting as progressive external ophthalmoplegia (PEO), is among the most common mitochondrial phenotypes. The purpose of this study is to better define the clinical phenotypes associated with ocular myopathy. This is a retrospective study on a large cohort from the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases". We distinguished patients with ocular myopathy as part of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy), and then PEO with isolated ocular myopathy from PEO-plus when PEO was associated with additional features of multisystemic involvement. Ocular myopathy was the most common feature in our cohort of mitochondrial patients. Among the 722 patients with a definite genetic diagnosis, ocular myopathy was observed in 399 subjects (55.3%) and was positively associated with mtDNA single deletions and POLG mutations. Ocular myopathy as manifestation of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy, n=131) was linked to the m.3243A>G mutation, whereas the other "PEO" patients (n=268) were associated with mtDNA single deletion and Twinkle mutations. Increased lactate was associated with central neurological involvement. We then defined, among the PEO group, as "pure PEO" the patients with isolated ocular myopathy and "PEO-plus" those with ocular myopathy and other features of neuromuscular and multisystem involvement, excluding central nervous system. The male proportion was significantly lower in pure PEO than PEO-plus. This study reinforces the need for research on the role of gender in mitochondrial diseases. The phenotype definitions here revisited may contribute to a more homogeneous patient categorization, useful in future studies and clinical trials.

Crimean-Congo Hemorrhagic Fever in Humanized Mice Reveals Glial Cells as Primary Targets of Neurological Infection.

Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral hemorrhagic disease seen exclusively in humans. Central nervous system (CNS) infection and neurological involvement have also been reported in CCHF. In the current study, we inoculated NSG-SGM3 mice engrafted with human hematopoietic CD34+ stem cells with low-passage CCHF virus strains isolated from human patients. In humanized mice, lethal disease develops, characterized by histopathological change in the liver and brain. To date, targets of neurological infection and disease have not been investigated in CCHF. CNS disease in humanized mice was characterized by gliosis, meningitis, and meningoencephalitis, and glial cells were identified as principal targets of infection. Humanized mice represent a novel lethal model for studies of CCHF countermeasures, and CCHF-associated CNS disease. Our data suggest a role for astrocyte dysfunction in neurological disease and identify key regions of infection in the CNS for future investigations of CCHF.

Impact of pain on cognitive functions in primary Sjögren syndrome with small fiber neuropathy: 10 cases and a literature review.

Primary Sjögren syndrome (pSS) is a chronic systemic autoimmune disease characterized by xerophthalmia, xerostomia, and potential peripheral or central neurological involvement. In pSS, the prevalence of cognitive disorders is generally sparse across literature and the impact of pain on cognitive profile is unclear. The aim of this study was to determine the relation between pain, cognitive complaint, and impairment in a very homogenous population of 10 pSS patients with painful small fiber neuropathy (PSFN) and spontaneous cognitive complaint. Neurological exam, neuropsychological assessment, clinical evaluation measuring pain level, fatigue, anxiety, depression, and cognitive complaint were performed. Our results showed that 100% of patients had cognitive dysfunction especially in executive domain (80%). The most sensitive test was the Wisconsin Card Sorting Test (WCST), abnormal in 70% of our population. Moreover, we found clear cut significant correlations between pain levels and 3 measures of WCST: the number of errors (R = –0.768, P = .0062), perseverations (R = 0.831, P = .0042), and categories (R = 0.705, P = .02). In the literature review, the impact of pain is underexplored and results could be discordant. In a homogeneous cohort of pSS patients with PSFN, a cognitive complaint seems to be a valid reflection of cognitive dysfunction marked by a specific executive profile found with the WCST. In this preliminary study, this profile is linked to the level of pain and highlights that an appropriate management of pain control and a cognitive readaptation in patients could improve the quality of life.

Long term effects of enzyme replacement therapy in an Italian cohort of type 3 Gaucher patients

BackgroundThe chronic neuropathic form of Gaucher disease (GD3) is characterised by hepatosplenomegaly, anaemia, thrombocytopenia, bone alterations and central neurological involvement. Enzyme replacement therapy (ERT) has been demonstrated to be effective in non neuropathic Gaucher disease, but long term results in patients with GD3 are still limited and contrasting. A possible role of genotype in determining the response to ERT has been hypothesised. Patients and methodsAll patients affected by GD3, treated with ERT, and followed-up in 4 different Italian centres (Udine, Catanzaro, Sassari and Florence) were included. Data on clinical conditions, laboratory values, neurological and neuropsychological examinations, radiological and electrophysiological features were collected retrospectively from clinical records. ResultsTen patients (6 females, 4 males) with four different genotypes (L444P/L444P, L444P/F231I, P159T/unknown, C.115+1G>A/N188S) were identified. They received ERT infusions from 3 to 21years. Haematological parameters and organomegaly improved/normalised in all patients. Three patients showed severe progressive skeletal deformities. 6/10 patients were neurologically asymptomatic when they started ERT for systemic symptoms. During the follow-up, 2/6 developed an important central nervous system disease; 2/6 developed mild central symptoms; and 2/6 did not show any neurological symptom after 5, and 20years of treatment respectively, despite the presence of epileptiform abnormalities at the electroencephalogram. Overall, neurological involvement worsened over time in 6/10 patients, 3 of whom developed progressive myoclonic encephalopathy and died. ConclusionsERT improved the systemic manifestations in patients with GD3, but was not able to counteract the progression of neurological symptoms in the long term.

Polyarteritis nodosa with central and peripheral neurological involvement

Polyarteritis nodosa with central and peripheral neurological involvement

Numbness in the Tip of the Tongue and Lower Lip Caused by Thalamic Hemorrhage

Although patients with isolated oral syndrome or facial sensory loss following stroke of thalamic ventroposteromedial (VPM) nucleus have been reported, there have been no reports of numbness in the tip of the tongue and lower lip. Furthermore, symptoms in the tip of the tongue caused by stroke are typically characterized as gustatory sensory disturbances. A 62-year-old hypertensive man experienced an acute onset of severe numbness in the left tip of the tongue and ipsilateral lower lip. Neurological examination revealed no other abnormalities except for the aforementioned numbness. Head computed tomography showed a small hematoma in the medial part of the right thalamus, most likely within the VPM nucleus. The somatosensory impulse of the tongue is conveyed via the lingual nerve, and it reaches the contralateral medial VPM proper via the trigeminal spinal nucleus. Therefore, thalamic stroke mainly involving the medial VPM proper has the potential to elicit numbness in the tip of the tongue. A major portion of the VPM nucleus is vascularized by the inferolateral arteries. The inferolateral arteries vary greatly in the number and position of the arteries and their tributaries, and small-vessel disease in this territory can present with diverse symptoms because of this complexity. These findings indicate that central neurological involvement should not be overlooked in the case of sensory disturbance restricted to the tip of the tongue and lip.

Central and peripheral neurological involvement in monoclonal gammopathies of undetermined significance

Several studies have suggested a pathogenetic role of paraproteinaemias in PNS damage. Over the few last years, the presence of symptomatic or subclinical PNS lesions in CNS diseases like multiple sclerosis has been described. On the other hand, CNS demyelinating lesions and cervical atrophy have been re- ported in patients affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Very few cases of MGUS associated with CNS disease alone or with both CNS and PNS disease have been re- ported. Since 1999, we have been studying 16 patients (8 M, 8 F), with a mean age 60.2 ± 13.4, affected by MGUS associated with symptomatic neurological central and/or peripheral diseases. Patients affected with lymphomas, lupus erithematosus and other immunological diseases were excluded. Involvement of both PNS and CNS was not associated to a particular type of paraproteinemia: monoclonal IgM were found in 8 patients; monoclonal IgG in 6 patients and mono- clonal IgA in 1 patient and Igl in 1 patient. High anti- nervous system autoantibodies were found in 10/16 patients and antiMAG antibodies were detected in patients with paraproteinemic demyelinating neuropathy (PDN). High reactivity anti-nervous system might support the hypothesis of a pathogenetic role of MGUS in these neurological diseases. Nevertheless, at present, we cannot exclude that there is only a circumstantial association between MGUS and neurological damages, particularly concerning CNS.