Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system

Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon neoplasms derived from melanocytes that normally can be found in the leptomeninges. They cover a spectrum of malignancy grades ranging from low-grade melanocytomas to lesions of intermediate malignancy and overtly malignant melanomas. Characteristic genetic alterations in this group of neoplasms have not yet been identified. Using direct sequencing, we investigated 19 primary melanocytic lesions of the CNS (12 melanocytomas, 3 intermediate-grade melanocytomas, and 4 melanomas) for hotspot oncogenic mutations commonly found in melanocytic tumors of the skin (BRAF, NRAS, and HRAS genes) and uvea (GNAQ gene). Somatic mutations in the GNAQ gene at codon 209, resulting in constitutive activation of GNAQ, were detected in 7/19 (37%) tumors, including 6/12 melanocytomas, 0/3 intermediate-grade melanocytomas, and 1/4 melanomas. These GNAQ-mutated tumors were predominantly located around the spinal cord (6/7). One melanoma carried a BRAF point mutation that is frequently found in cutaneous melanomas (c.1799 T>A, p.V600E), raising the question whether this is a metastatic rather than a primary tumor. No HRAS or NRAS mutations were detected. We conclude that somatic mutations in the GNAQ gene at codon 209 are a frequent event in primary melanocytic neoplasms of the CNS. This finding provides new insight in the pathogenesis of these lesions and suggests that GNAQ-dependent mitogen-activated kinase signaling is a promising therapeutic target in these tumors. The prognostic and predictive value of GNAQ mutations in primary melanocytic lesions of the CNS needs to be determined in future studies.     

GNA11 and N‐RAS mutations: alternatives for MAPK pathway activating GNAQ mutations in primary melanocytic tumours of the central nervous system

M. Gessi, J. Hammes, L. Lauriola, E. Dörner, J. Kirfel, G. Kristiansen, A. zur Muehlen, D. Denkhaus, A. Waha and T. Pietsch (2013) Neuropathology and Applied Neurobiology 39, 417–425 GNA11 and N‐RAS mutations: alternatives for MAPK pathway activating GNAQ mutations in primary melanocytic tumours of the central nervous system Aim: Primary melanocytic tumours are uncommon neoplasms of the central nervous system. Although similarities with uveal melanomas have been hypothesized, data on their molecular features are limited. Methods: In this study, we investigated the mutational status of BRAF^V600E, KIT, GNAQ, GNA11, N‐RAS and H‐RAS in a series of 19 primary melanocytic tumours of the central nervous system (CNS). Results: We identified six cases harbouring mutations in the hotspot codon 209 of the GNAQ gene and two cases with mutations in the hotspot codon 209 of the GNA11 gene. Two mutations in codon 61 of N‐RAS were also found. In the single strand conformation polymorphism (SSCP) analysis, no shifts corresponding to BRAF^V600E mutations or suggesting activating mutations in the KIT gene were observed. Conclusions: In primary melanocytic tumours of the CNS, GNA11 and N‐RAS mutations represent a mechanism of MAPK pathway activation alternative to the common GNAQ mutations. On the other hand, BRAF^V600E mutations and activating KIT mutations seem to be absent or very rare in these tumours.     

Intraventricular melanocytoma diagnosis confirmed by gene mutation profile

Primary leptomeningeal melanocytic tumors (PLMTs) are rare. They usually arise along the spinal cord and at the skull base. Here we report on a patient with a very rare intraventricular melanocytoma. Histologically, a melanocytic tumor was clearly diagnosed. However, to make the uncommon diagnosis of an intraventricular melanocytoma, metastatic melanoma needed to be excluded. Next generation sequencing covering gene mutations that may occur in PLMTs and cutaneous melanoma was performed. The unique gene mutation profile detected, consisting of an activating CYSLTR2 L129Q mutation and EIF1AX G9R mutation and a lack of mutations in genes known to occur in metastatic melanoma (i.e. BRAF or NRAS) confirmed the diagnosis of an intraventricular melanocytoma. This case report is the second intraventricular melanocytoma published to date and demonstrates the value of applying novel genetic assays to make this diagnosis.     

Clinical characteristics and treatment outcomes of pigmented tumors in central nervous system: Focusing on melanocytic tumors

Pigmented tumors are rare neoplasm of central nervous system. Melanocytic tumor, including primary and metastatic lesions, is the most common type. Owing to the rarity, the differential diagnosis of pigmented tumors and clinical management of melanocytic tumor remain challenge. Therefore, focusing on melanocytic tumors, the clinical, radiological, histopathological features and treatment outcomes were presented and analyzed in this study. We identified 22 melanocytic tumors, 2 melanotic medulloblastomas, 2 melanotic ependymomas and 1 melanotic schwannoma. Compared with metastatic melanocytic tumors (MMTs), primary melanocytic tumors (PMTs) were characterized by younger age (36.11 ± 17.96 vs. 51.69 ± 12.58 years, p = 0.0262), lower possibility to be multiple lesions (11.1%vs. 61.5%, p = 0.0306), higher proportion of hypointensity on T2-weighted images (66.7% vs. 15.4%, p = 0.0260) and higher frequency in black appearance (77.8% vs. 23.1%, p = 0.0247). During the follow-up, 4 PMTs and 11 MMTs (71.4%) experienced tumor progression. PMTs had better prognosis than MMTs that progression-free survival (PFS) rate of PMT was 50.0% but decreased to 23.1% for MMTs at 12 months (p = 0.0123). Cox proportional hazards regression revealed that multiplicity of tumor was an independent predictor for PFS. None of patient with multiple tumors was in PFS after 12 months’ follow-up whereas PFS rate was 40.5% for single tumor (p = 0.0002). In conclusion, radiological appearances, especially hypointensity on T2-weighted images, might be an indication for PMT. MMTs are more likely to be multiple intraparenchymal masses in elder patients located in supratentorial region. Current treatments included operation, radiotherapy and chemotherapy are not competent to control tumor progression and other therapeutic modalities are urgently needed.     

Intermediate grade meningeal melanocytoma of cervical spine

Background  Meningeal melanocytoma is a rare, benign melanotic tumor of the leptomeninges, which occurs anywhere in the cranial or spinal regions but most commonly in supratentorial and thoracic spine regions. The literature on this entity consists of case reports; therefore, there is no agreement on the most effective therapy of this tumor, although total excision seems to be the best therapeutic option. Case history  We report a 17-year-old girl with intermediate grade meningeal melanocytoma involving the C6 nerve root with spinal cord compression resulted in progressive tetraparesis. Clinical and radiological examinations suggested the possibility of an intradural extramedullary solid mass. The tumor was removed subtotally through cervical laminotomy followed by rapid improvement of most neurological deficits. This tumor was unusual because of its very hyperintense homogenous signal on T1-weighted images, invasion of the arachnoid membrane, and extension into the neural foramina. Black dots on the surface of the cord were thought to represent an organized blood clot until the frozen section suggested a melanocytic tumor. Discussion  We discuss the distinction of meningeal melanocytoma from other melanocytic tumors of the leptomeninges. Conclusion  Melanocytic tumors should be considered in the differential diagnosis when a hyperintense lesion of the leptomeninges is identified on T1-weighted images or a very dark mass similar to charcoal or organized hematoma is found in the surgical field. The best management is complete tumor resection, but radiotherapy is reserved in cases of subtotal resection and multiple lesions. Locally aggressive nature of tumor and possibility of recurrence warrant regular follow-up.     

Leptomeningeal neurons are a common finding in infants and are increased in sudden infant death syndrome

Developmental abnormalities of the brain, in particular, the brainstem potentially affecting centers for breathing, circulation and sleep regulation, are thought to be involved in the etiology of sudden infant death syndrome (SIDS). In order to investigate whether leptomeningeal neurons could serve as morphological indicators for a developmental failure or retardation in cerebral maturation, we evaluated the density of isolated leptomeningeal neurons (without associated glia) in 15 brain regions of 24 SIDS and 8 control cases, representing part of the German Study on sudden infant death. Leptomeningeal neurons were encountered in 79% of SIDS and 68% of control cases. More leptomeningeal neurons in SIDS versus control cases were found in lower pons (p = 0.002), upper pons (p = 0.016), cerebellar hemispheres (p = 0.012), lower medulla oblongata (p = 0.039), and temporal lobe (p = 0.041). Summarizing the data according to gross anatomical region of origin (i.e., brainstem, cerebellum or cerebrum), higher numbers of leptomeningeal neurons in SIDS cases were only found in the brainstem (p = 0.006 vs. 0.13 and 0.19, respectively). Our data show that single leptomeningeal neurons are present in most normal infantile brains. The age-dependent increase of leptomeningeal neurons among SIDS cases may either (a) represent a delayed maturation or retardation, i.e., a later or slower reduction of neurons or a delayed peak in occurrence (shift toward an older age), or (b) may be interpreted as a generally increased occurrence of leptomeningeal neurons among SIDS cases as a result of a diffuse developmental abnormality during central nervous system maturation.     

Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology

Isocitrate dehydrogenase 1 (IDH1) mutations are frequent in astrocytomas, oligoastrocytomas and oligodendrogliomas. We previously reported the generation of a mutation-specific antibody that specifically detects R132H mutated IDH1 protein (clone H09). Here, we investigate the feasibility of H09 immunohistochemistry to differentiate between oligodendrogliomas/oligoastrocytomas and other tumors with similar morphology. A total of 274 brain tumors presenting with focal or extensive clear cell morphology were investigated. High numbers of H09-positive cases were observed in adult grade II oligodendrogliomas (67 of 74, 91%), grade III oligodendrogliomas (65 of 69, 94%), grade II oligoastrocytomas (11 of 14, 79%) and grade III oligoastrocytomas (10 of 11, 91%). All cases of pediatric oligodendrogliomas (n = 7), neurocytomas (n = 41, 35 central, 4 extraventricular, 2 cerebellar liponeurocytomas), dysembryoplastic neuroepithelial tumors (n = 21), clear cell ependymomas (n = 8), clear cell meningiomas (n = 9) as well as 12 primary glioblastomas with oligodendroglial differentiation and 5 pilocytic astrocytomas with oligodendroglial-like differentiation were negative for H09 immunohistochemistry. Three oligodendrogliomas with neurocytic differentiation had evidence of IDH1/IDH2 mutations either by H09 immunohistochemistry or direct sequencing. We conclude that in tumors with an oligodendroglioma-like morphology, binding of H09 is highly specific for oligodendrogliomas or oligoastrocytomas and substantially helps in the discrimination from other clear cell tumors. Negative H09 immunohistochemistry of an adult oligodendroglioma or oligoastrocytoma should prompt the consideration of other clear cell neoplasms. Further, our observations firmly assign oligodendrogliomas with neurocytic differentiation to the group of oligodendrogliomas and demonstrate that H09 is especially helpful for the difficult discrimination of such lesions from extraventricular neurocytomas.     

Isolated angiitis of the CNS and bacterial endocarditis: similarities and differences

Both isolated angiitis of the central nervous system (IAN) and bacterial endocarditis (BE) may present with similar clinical and auxiliary findings. The differentiation is extremely important because of the different treatment regimens. We compared the findings of six patients with biopsy-proven IAN with the data of six patients with BE. Patients with IAN were younger (27–62 years) and presented with multiple strokes (n = 4), intracerebral hemorrhage (n = 1), epileptic seizures (n = 2), or encephalopathy (n = 1). All IAN patients had pathologic cerebrospinal fluid (CSF) findings (pleocytosis n = 5; protein elevation n = 4), and angiography revealed multilocular stenoses in two cases while digital subtraction angiography was normal in four. BE patients (32–77 years) presented multiple (n = 3) or single ischemic strokes (n = 2) or encephalopathy and headache (n = 2). While all patients showed inflammatory serum findings (C-reactive protein n = 6, leucocytosis n = 4), CSF-pleocytosis was present in two cases only. Angiography revealed a vasculitic pattern in two patients. The diagnosis of BE was etablished based on transesophageal echocardiography and blood cultures. Leptomeningeal and brain biopsies performed in two cases were normal. Both IAN and BE may present multiple strokes and encephalopathy. The frequency of a vasculitic pattern in angiography is similar in both conditions. While inflammatory serum findings are the rule in BE, pathologic CSF findings were present in all IAN patients. Transesophageal echocardiography and blood cultures should be performed in order to diagnose or exclude BE. Without brain biopsy, immunosuppressive therapy may be dangerous in suspected IAN.     

Phenotype variability and histopathological findings in centronuclear myopathy due to DNM2 mutations

Autosomal-dominant centronuclear myopathy (CNM) due to mutations in the dynamin 2 gene (DNM2) is a rare congenital myopathy histopathologically characterized by centrally located nuclei and a radial arrangement of sarcoplasmic strands around the central nuclei. A total of 1,582 consecutive muscle biopsies of adult patients (age ≥18 years) were screened for morphologically characteristic signs of CNM. Patients with CNM were screened for mutations in DNM2. Clinical data and complementary neurophysiologic, respiratory, cardiac, and muscle MRI data in these patients were analyzed. Six index patients had histopathological signs of CNM (0.38%). Three had the heterozygous p.R465W and 2 siblings the heterozygous p.E368K DNM2 mutation. In 2 patients mutational screening for DNM2, BIN1, MTM1, and RYR1 was negative. Apart from the siblings, there was no positive history, parental mutation screening in 2 cases was negative. Both the percentage of muscle fibers with centralized nuclei and the ratio of muscle fibers with centralized to internalized nuclei were higher in DNM2-CNM compared to non-DNM2-CNM (50% vs. 18% and 94% vs. 63%). The onset was already neonatal or in infancy in 3/5 patients with DNM2 mutation. Symptoms in DNM2-CNM included bilateral ptosis (n = 3), paresis of the external ocular muscles (n = 2), axonal neuropathy (n = 4), restrictive ventilatory involvement (n = 5), and contractures (n = 5), including muscular torticollis (n = 1) and masticatory muscles (n = 2). DNM2-CNM patients and non-DNM2-CNM patients could not be distinguished by clinical features. DNM2-CNM often shows de novo mutations. In addition to the feature of radial sarcoplasmic strands, the ratio of centrally to internalized nuclei might help to differentiate DNM2-CNM from other forms of CNM. Other genes than currently known seem to cause the clinical and histopathological phenotype of CNM.     

Leptomeningeal anastomosis and early ischemic lesions on diffusion-weighted imaging in male murine focal cerebral ischemia

Leptomeningeal anastomosis is a key factor for determining early ischemic lesions on diffusion-weighted imaging (DWI) in human stroke. However, few studies have validated this relationship in an experimental model. This study sought to clarify the involvement of leptomeningeal anastomosis in early ischemic lesions using a murine model. Adult male C57BL/6 mice were subjected to unilateral common carotid artery (CCA) occlusion or sham surgery. Seven or 14 days later, the middle cerebral artery (MCA) was occluded for 45 min. In the first experiment, the leptomeningeal collaterals were visualized using magnetic resonance imaging (MRI) DWI. In the second experiment, DWI was performed immediately after MCA occlusion, and the infarct sizes were determined 24 hr after recirculation. Unilateral CCA occlusion reduced the size of early ischemic lesions, enlarged the pial vessel diameter, and mitigated infarct size. The relationship between the DWI lesion size and pial vessel diameter was significant (r = 0.84, p < 0.01). The association between infarct size and DWI lesion size was also significant (r = 0.96, p < 0.01). In conclusion, involvement of the collateral circulation in early ischemic lesions was evident in the murine model. Both MRI and evaluation of leptomeningeal anastomosis could be used to develop a novel strategy targeting enhancement of the collateral circulation.     

Characterizing SOD1 mutations in Spain: The impact of genotype,age and sex in the natural history of the disease

Background and purpose

The aim of this study was to describe the frequency and distribution of SOD1 mutations in Spain, and to explore factors contributing to their phenotype and prognosis.

Methods

Seventeen centres shared data on amyotrophic lateral sclerosis (ALS) patients carrying pathogenic or likely pathogenic SOD1 variants. Multivariable models were used to explore prognostic modifiers.

Results

In 144 patients (from 88 families), 29 mutations (26 missense, 2 deletion/insertion and 1 frameshift) were found in all five exons of SOD1, including seven novel mutations. A total of 2.6% of ALS patients (including 17.7% familial and 1.3% sporadic) were estimated to carry SOD1 mutations. The frequency of this mutation varied considerably among regions, due to founder events. The most frequent mutation was p.Gly38Arg (n = 58), followed by p.Glu22Gly (n = 11), p.Asn140His (n = 10), and the novel p.Leu120Val (n = 10). Most mutations were characterized by a protracted course, and some of them by atypical phenotypes. Older age of onset was independently associated with faster disease progression (exp[Estimate] = 1.03 [0.01, 0.05], p = 0.001) and poorer survival (hazard ratio 1.05 [1.01, 1.08], p = 0.007), regardless of the underlying mutation. Female sex was independently associated with faster disease progression (exp[Estimate] = 2.1 [1.23, 3.65], p = 0.012) in patients carrying the p.Gly38Arg mutation, resulting in shorter survival compared with male carriers (236 vs. 301 months).

Conclusions

These data may help to evaluate the efficacy of SOD1 targeted treatments, and to expand the number of patients that might benefit from these treatments.     

Primary melanocytic tumors of the central nervous system: a neuroradiological and clinicopathological study of five cases and brief review of literature

Primary melanocytic tumors of the central nervous system (CNS) are uncommon lesions. These lesions arise from the melanocytes located within leptomeninges and include diffuse melanocytosis and meningeal melanomatosis (seen in neurocutaneous melanosis), melanocytoma, and malignant melanoma. To study, the clinical course, neuroradiological features, morphology and immunohistochemistry of primary melanocytic tumor of CNS. Demographic, clinical and surgico-pathologic findings of five patients with melanocytic tumors seen between 1996 and 2003 were studied. In this study, five cases of primary melanocytic tumors have been reported: four cases of malignant melanoma and one case of melanocytoma. Three of the 5 cases were intracranial and 2 were spinal. The mean age in the present study was 26 years. Presenting features varied according to the location. Primary melanocytic tumor of CNS are rare. Whenever possible, complete surgical excision is the best treatment.     

Infraspinatus muscle palsy involving suprascapular nerve,brachial plexus or cervical roots related to inflammatory or mechanical causes: Experience of 114 cases

ObjectivesTo report a large series of neurogenic infraspinatus muscle (ISM) palsy, in order to improve knowledge of diagnosis, diverse etiologies and care management.MethodsClinical and electrodiagnostic (EDX) data for 114 cases of ISM palsy were collected over a 21-year period. Cases were attributed to 4 clinical conditions: (1) isolated suprascapular nerve mononeuropathy (n = 48), (2) multiple mononeuropathies (n = 33), (3) plexus lesions (n = 17), and (4) cervical radiculopathy (n = 16). These were related to 2 mechanisms: inflammatory (dysimmune) and mechanical.ResultsGroup 1 cases were younger, had the most severe ISM palsies, were mostly related to inflammatory lesions (81%) such as neuralgic amyotrophy (NA), and frequently had delayed diagnosis because disability was mild. Group 2 cases were all related to inflammatory lesions and had slightly less severe ISM palsies that were frequently hidden by winged scapula. In groups 3 and 4, ISM palsies were milder and all cases were related to mechanical lesions such as brachial plexus trauma or C4-C5-C6 radiculopathy. In these cases, deltoid and ISM palsies were equal in frequency and severity whereas biceps brachii impairment was less frequent and much milder. Deltoid palsy frequently appeared predominant as compared with ISM palsy, because upper limb elevation palsy was more disabling than external rotation palsy.ConclusionsISM palsy is a rare condition, often under-diagnosed and misidentified. The 4 main conditions of ISM palsy may be recognized by careful clinical, EDX and other examinations when necessary. Analysis of the present series highlights some clinical and EDX points that should help non-specialist and even specialist clinicians who are faced with this rare condition, to distinguish mechanical and inflammatory causes, and thus adapt patient management accordingly.     

The clinical course of idiopathic acute transverse myelitis in patients from Rio de Janeiro

The aim of this study was to describe the demographic, clinical and laboratory features of idiopathic acute transverse myelitis (IATM). Patients with non-compressive ATM receiving care at Hospital da Lagoa, Rio de Janeiro (Brazil) between 2000 and 2008 were selected. Of the 70 cases of acute myelopathies, the idiopathic form was identified in 41 following exclusion of the cases associated with systemic lupus erythematosus (n = 1), Sjogren’s syndrome (n = 1), herpes zoster (n = 1), cytomegalovirus in an HIV-positive patient (n = 1), Schistosoma mansoni (n = 1), actinic myelitis (n = 1), infectious myelitis of unknown etiology (n = 2) and those that, following the first attack of myelitis, converted to NMO (n = 19) or to clinically defined MS (n = 2). Of the 41 cases of IATM, the majority of patients were female (68.3%) and white (65.9%). Median age at first myelitis was 37.0 ± 11.8 years. Over a median observation time of 36 months, 39.0% of patients remained monophasic, while recurrences occurred in 61.0% of cases. The number of ATM/patient ranged from one to seven. Among the recurrent cases the median time between the first and the second ATM was 12 months (range 1–150 months).The first myelitis was characterized mainly by partial myelitis with motor and sensorial dysfunction (63.4%). Complete and severe myelitis occurred more frequently among monophasic patients and partial myelitis with moderate dysfunction at onset in recurrent cases; however, over the long-term, dysfunction and disability were mild in both groups. Serial spine MRI confirmed spinal cord inflammation in 92.0% of cases and extensive spinal cord lesion was identified in 61.0%. Brain MRI was normal or not suggestive of MS in 94.4% of cases. CSF showed pleocytosis in 41.2%, increased IgG index in 24.0% and oligoclonal bands in 38.0% of 34 patients tested. Abnormal visual evoked potentials occurred in 11.5% of 26 patients. Positivity for anti-AQP4 was found in 23.5% of the 17 cases tested, suggesting limited forms of NMO. This study suggests some new aspects of the clinical course of IATM such as the high conversion rate to NMO, the predominance of women and a higher frequency of recurrent forms.     

The epidemiology of CuZn-SOD mutations in Germany: a study of 217 families

We screened 217 patients from Germany (n = 213), Austria (n = 2) and Switzerland (n = 2) with a positive family history for amyotrophic lateral sclerosis (ALS) for mutations in the copper/zinc superoxide dismutase (SOD1) gene. We found that 13% of the families tested carried mutations. By analyzing inheritance, we detected a clear-cut co-segregation in 5 of the 28 families; however, in two families with an established mutation, co-segregation was absent. In Germany, the R115G mutation is comparatively frequent and exhibits a specific aggressive phenotype. The L144F mutation, which is the most prevalent mutation in the Balkan countries, and the D90A mutation which is the most frequent SOD1 mutation globally, seem to be the second most common disease-causing mutations in Germany.     

Genetic variation of the mitochondrial complex I subunit NDUFV2 and Parkinson's disease

NADH dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), encoding a subunit of mitochondrial complex I, is a candidate gene for several neuronal diseases; schizophrenia, bipolar disorder and Parkinson disease (PD). We screened the entire coding region of NDUFV2 in 33 familial PD patients of North African Arab-Berber ethnicity in which all known genetic forms of PD had been excluded. We detected one novel substitution p.K209R (c.626A > G) in one PD proband. Segregation analysis within the family is inconclusive due to small sample size, but consistent with an autosomal dominant mode of inheritance. Subsequent screening of this mutation in ethnically matched sporadic PD patients (n = 238) and controls (n = 371) identified p.K209R in one additional patient. The clinical features of the mutation carriers revealed a mild form of parkinsonism with a prognosis similar to idiopathic PD. Our findings suggest further studies addressing the role of NDUFV2 variation in PD may be warranted.     

Primary atypical melanocytoma arising from the cavernous sinus in a child

Introduction

Primary melanocytic lesions of the central nervous system originate from leptomeningeal melanocytes, with a spectrum ranging from well-differentiated benign meningeal melanocytomas to malignant melanomas. Atypical melanocytomas are borderline tumors, which have clinical and pathological characteristics between benign melanocytomas and malignant melanomas. Melanocytomas are rare in children and infrequently arise from the cavernous sinus. Approximately five patients with such an origin site have been reported.

Materials and methods

We report a 15-year-old girl with an atypical melanocytoma arising from the cavernous sinus. She underwent partial resection of the tumor and postoperative gamma knife surgery (GKS). She is stable 39 months after surgery.

Conclusion

We discuss the first pediatric case with an intracranial atypical melanocytoma arising from the cavernous sinus.

     

Central pontine and extrapontine myelinolysis: from epileptic and other manifestations to cognitive prognosis

The objective of this study is to review the presentation, outcome and aetiology of central pontine and extrapontine myelinolysis (CPEPM) in a tertiary hospital center. The study method is a case series and included identification of patients from University of Montreal Health Centre archives database (1995–2007). All diagnoses were confirmed by neuroimaging or brain autopsy. Twelve individuals (25–66 years old) presented heterogeneous manifestations. Co-morbidities included diabetes insipidus (n = 2), haemodialysis (n = 1), cirrhosis (n = 3), gastroenteritis (n = 2) and potomania (n = 1). Aetiologies included rapid correction of severe hyponatremia (n = 6)/acute hypernatremia (n = 1); immediate (n = 2) or remote (n = 1 with recurrent cirrhosis) orthotopic liver transplantation (OLT) with tacrolimus-induced immunosuppression (n = 3); and chronic alcoholism (n = 4, two with hyponatremia). Four individuals died acutely. Two were lost to follow-up. Six had good motor or cerebellar recovery. Neuropsychological evaluations (n = 5/6) revealed a subcortical/frontal dysfunction. Cognitive impairment represented the major remaining lasting sequel (n = 4). Three salient clinical syndromes were observed: (1) predominant cerebellar presentation in individuals with alcoholism (n = 4); (2) significant alteration of consciousness at presentation (n = 4), all resulting in death (OLT, n = 3); (3) seizures persisting after natremia correction (n = 2). Clinical presentation of CPEPM is heterogeneous and can even include seizures. Cognitive impairment should be screened as it is a significant factor limiting return to normal life.