Early hydrocephalus in Listeria meningitis: Case report and review of the literature.

Listeria monocytogenes is a gram-positive bacterium with a predilection to infect the central nervous system, often affecting immunocompromised or elderly patients. The most common manifestations are meningitis and rhomboencephalitis. We report two cases of Listeria meningitis complicated by acute hydrocephalus several days after presentation and we further review the literature of similar cases. We conclude that acute hydrocephalus is a significant, not often recognized, complication of Listeria meningitis, usually occurring several days from onset when coverage did not include anti-Listeria antimicrobials. In high risk patients, meningitis combined with acute hydrocephalus is suggestive of LM infection.

EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.

BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of two particularly complex groups of disorders, the ataxias and spastic paraplegias. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.

EFNS guidelines on the molecular diagnosis of mitochondrial disorders.

OBJECTIVES: These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools. BACKGROUND: Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version. SEARCH STRATEGY: To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work-up of MIDs. RECOMMENDATIONS: The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.

EFNS guidelines on the molecular diagnosis of neurogenetic disorders: general issues, Huntington's disease, Parkinson's disease and dystonias.

BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. Since the publication of the first two EFNS-guideline papers on the molecular diagnosis of neurological diseases in 2001, rapid progress has been made in this field, necessitating an updated series of guidelines. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of Huntington's disease, Parkinson's disease and dystonias as well as a general introduction to the topic. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.

Central nervous system involvement in indolent lymphomas.

BACKGROUND: Central nervous system (CNS) involvement, a well-recognized complication of aggressive non-Hodgkin's lymphomas (NHL), has rarely been reported in indolent lymphomas. Large series have reported this complication in 3% of indolent NHLs, generally following histological transformation. PATIENTS AND METHODS: We retrospectively reviewed the disease characteristics and clinical course in seven patients (six females, one male) with indolent B-cell lymphomas who developed CNS involvement during various stages of their illness. RESULTS: The median ages at diagnosis of systemic and CNS lymphoma were 60 and 63 years, respectively. Histologies were: small lymphocytic lymphoma (two), follicular lymphoma grade I (two), follicular lymphoma grade II (two) and unclear low-grade histology (one). There were diverse neurological symptoms. Two patients had parenchymal involvement, three had leptomeningial involvement and two had both. Systemic lymphoma was found in all patients, all but one having bone marrow involvement. Four patients had a transformation to high-grade histology. Six patients were treated with systemic and intra-cerebrospinal fluid chemotherapy, and two received radiotherapy as well. Five patients achieved CNS response. Survival was 1-9 years for treated patients (median 2 years). Three patients died of CNS disease. CONCLUSIONS: CNS involvement is a rare and unexpected complication of indolent NHL, which should be considered in the differential diagnosis of patients presenting with new neurological signs. This condition is treatable and some patients have a long clinical course.

Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.

Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C.

PURPOSE: Niemann-Pick disease type C (NP-C) is an autosomal recessive lipid storage disease manifested by an impairment in cellular cholesterol homeostasis. The clinical phenotype of NP-C is extremely variable, ranging from an acute neonatal form to an adult late-onset presentation. To facilitate phenotype-genotype studies, we have analyzed multiple Israeli NP-C families. METHODS: The severity of the disease was assessed by the age at onset, hepatic involvement, neurological deterioration, and cholesterol esterification studies. Screening of the entire NPC1 coding sequence allowed for molecular characterization and identification of disease causing mutations. RESULTS: A total of nine NP-C index cases with mainly neurovisceral involvement were characterized. We demonstrated a possible link between the severity of the clinical phenotype and the cholesterol esterification levels in fibroblast cultures following 24 hours of in vitro cholesterol loading. In addition, we identified eight novel mutations in the NPC1 gene. CONCLUSIONS: Our results further support the clinical and allelic heterogeneity of NP-C and point to possible association between the clinical and the biochemical phenotype in distinct affected Israeli families.

Pharmacokinetics of methotrexate in cerebrospinal fluid and serum after osmotic blood-brain barrier disruption in patients with brain lymphoma.

OBJECTIVE: To evaluate the pharmacokinetics of methotrexate in ventricular cerebrospinal fluid and serum after osmotic blood-brain barrier disruption and intra-arterial administration compared with intravenous or simple intra-arterial infusion in patients with primary central nervous system lymphoma. METHODS: Serum and ventricular cerebrospinal fluid were sampled after methotrexate administration in 12 patients. Blood-brain barrier disruption was induced on 2 sequential days by mannitol (25%) infusion delivered to the vertebral or internal carotid artery territories followed by intra-arterial methotrexate (dose, 1.4 g/m2; 47 treatments). Sixteen treatments were given without barrier disruption by intravenous (3.5 g/m2; nine treatments) or intra-arterial (2.8 g/m2; seven treatments) infusion. RESULTS: Ventricular cerebrospinal fluid-methotrexate peak levels after blood-brain barrier disruption of the vertebral and the internal carotid arteries territories were 19.3 +/- 2.9 and 8.5 +/- 0.7 micromol/L (P < .001), and the area under the curve from time 0 to infinity was 178.0 +/- 21.3 and 110.0 +/- 12.4 [micromol/L x h, respectively (P < .01). No significant differences were observed in serum levels. After intra-arterial infusion was performed without disruption, the serum peak level was higher than that achieved by intravenous treatment (518.2 +/- 67.7 versus 180.6 +/- 31.8 micromol/L; P < .001). No differences were observed in cerebrospinal fluid concentrations, which dropped below 1 micromol/L at 6 hours. The cerebrospinal fluid/serum ratio [AUC(%)] of methotrexate after blood-brain barrier disruption was three to four times greater than that by systemic administration. CONCLUSION: Enhanced methotrexate delivery to the central nervous system can be attained by intra-arterial administration combined with osmotic disruption of the blood-brain barrier compared with simple intra-arterial or intravenous administration.

In vivo assessment of the window of barrier opening after osmotic blood-brain barrier disruption in humans.

OBJECT: Osmotic blood-brain barrier (BBB) disruption induced by intraarterial infusion of mannitol is used in conjunction with chemotherapy to treat human brain tumors. The time course to barrier closure, or the so-called therapeutic window, has been examined in animals but little information is available in humans. The authors, therefore assessed the time course to barrier closure after osmotic BBB disruption in humans. METHODS: Disruption of the BBB was demonstrated using 99mTc-glucoheptonate (TcGH) single-photon emission computerized tomography (SPECT) scanning in 12 patients who were treated monthly with combination chemotherapy in conjunction with BBB disruption. The primary diagnosis was primary central nervous system lymphoma in seven patients and primitive neuroectodermal tumors in five. The TcGH (20 mCi) was injected at 1- to 480-minute intervals after osmotic BBB disruption, and patients underwent SPECT scanning after 4 hours. A total of 38 studies was performed. Good-to-excellent BBB disruption was obtained in 29 procedures and poor-to-moderate disruption was seen in the other nine studies. The TcGH indices correlated with the degree of BBB disruption as measured postprocedure on contrast-enhanced CT scans (r = 0.852). Mean baseline TcGH indices were 1.02+/-0.07. For the group of patients with good-to-excellent disruptions the mean indices at 1 minute postdisruption measured 2.19+/-0.18. After 40 minutes no significant change was noted (mean index 2.13+/-0.2). Then the indices declined more steeply and at 120 minutes after the disruption the index was 1.36+/-0.02. A very slow decline was noted between 120 and 240 minutes after mannitol infusion. At 240 minutes the barrier was still open for all good-to-excellent disruptions (index 1.33+/-0.08) but at 480 minutes the mean indices had returned to the baseline level. CONCLUSIONS: Results of these in vivo human studies indicate that the time course to closure of the disrupted BBB for low-molecular-weight complexes is longer than previously estimated. The barrier is widely open during the first 40 minutes after osmotic BBB disruption and returns to baseline levels only after 6 to 8 hours following the induction of good or excellent disruption. These findings have important clinical implications for the design of therapeutic protocols.

Cerebrospinal fluid lactate dehydrogenase isoenzyme analysis for the diagnosis of central nervous system involvement in hematooncologic patients.

BACKGROUND: Central nervous system (CNS) involvement is common in hematooncologic diseases. The aim of the current study was to determine the diagnostic value of cerebrospinal fluid (CSF) lactate dehydrogenase (LDH) isoenzyme analysis for the diagnosis of CNS involvement in hematooncologic patients. METHODS: The study was comprised of 63 consecutive hematooncologic patients without previous CNS disease who underwent CSF examination as an integral part of their initial staging procedures (44 patients) or for the evaluation of neurologic symptoms (19 patients). Fifteen of these patients had CNS involvement by leukemia or lymphoma. The LDH isoenzyme pattern was established in the CSF of all patients and analyzed by the classification and regression trees (CART) method to construct a decision tree for the prediction of CNS involvement. An additional group of 30 consecutive patients comprised a validation set that was used for cross-validation of the CART-derived decision tree. RESULTS: A decision tree, with a single split at LDH5 >/= 2.8% for the prediction of CNS involvement, was constructed and validated by data from a validation set of patients. The decision tree had a sensitivity of 93% and a negative predictive value of 98%. One patient (1.6%) and 2 patients (6.6%) were misclassified in the derivation and validation sets, respectively. Overall, in the combined derivation and validation patient population, the decision tree misclassified 3.2% of patients, whereas CSF cytologic examination misclassified 4.3% of patients. CONCLUSIONS: Analysis of the LDH isoenzyme pattern in CSF fluid may be helpful in the evaluation of CNS involvement in patients with hematologic malignancies. The combination of CSF cytology and LDH isoenzyme analysis may improve the sensitivity of CSF cytology significantly.

Absence of mutations in ATM, the gene responsible for ataxia telangiectasia in patients with cerebellar ataxia.

Ataxia-telangiectasia (AT) is an autosomal recessive multisystem disorder presenting in childhood with progressive cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, radiosensitivity, and cancer predisposition. The gene for AT, designated ATM (AT, mutated) encodes a protein with a carboxy-terminal phosphoinositide-3 kinase domain which is involved in cell cycle checkpoints and other responses to genotoxic stress. Most of the patients with the classical AT phenotype are homozygous or compound heterozygous for severe mutations causing truncation or destabilization of the ATM protein. Patients with a milder forms of disease, called AT variants, have been found to be either homozygous for milder mutations or compound heterozygotes for null alleles and mild mutations. In order to define the clinical phenotype of patients homozygous (or compound heterozygotes) for other, milder mutations, we decided to search for ATM mutations in patients with either sporadic or familial idiopathic ataxia. Thirty-four patients with idiopathic cerebellar ataxia, aged 3-77 years, were screened for mutations in the ATM coding region. There were 12 familial cases. None of the patients had abnormal immunoglobulin or alpha-fetoprotein levels, and none had mutations in the ATM coding region. In this heterogeneous group of patients with cerebellar ataxia we found no mutations in the ATM gene. We conclude that mutations in the ATM gene are probably not a common cause for cerebellar ataxia other than AT.

Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene.

Adult polyglucosan body disease (APBD) is a late-onset, slowly progressive disorder of the nervous system caused by glycogen branching enzyme (GBE) deficiency in a subgroup of patients of Ashkenazi Jewish origin. Similar biochemical finding is shared by glycogen storage disease type IV (GSD IV) that, in contrast to APBD, is an early childhood disorder with primarily systemic manifestations. Recently, the GBE cDNA was cloned and several mutations were characterized in different clinical forms of GSD IV. To examine whether mutations in the GBE gene account for APBD, we studied 7 patients from five Jewish families of Ashkenazi ancestry. The diagnosis was based on the typical clinical and pathological findings, and supported by reduced GBE activity. We found that the clinical and biochemical APBD phenotype in all five families cosegregated with the Tyr329Ser mutation, not detected in 140 controls. As this mutation was previously identified in a nonprogressive form of GSD IV and was shown in expression studies to result in a significant residual GBE activity, present findings explain the late onset and slowly progressive course of APBD in our patients. We conclude that APBD represents an allelic variant of GSD IV, but the reason for the difference in primary tissue involvement must be established.

Intravascular lymphomatosis--an indolent or aggressive entity?

Intravascular lymphomatosis (IVL) is a rare malignancy characterized by neoplastic proliferation of lymphoid cells within the lumens of arteries, small veins and capillaries. We report four patients with IVL and review the recent world literature, relating to incidence, clinical features and possible therapy. In these cases diagnosis was established coincidentally in one patient after prostatectomy. This patient eventually had central nervous system involvement. In two other patients IVL was diagnosed from skin lesions. In the fourth case the diagnosis was established at post-mortem examination, where involvement of most organs was evident but particularly kidneys, myocardium, gastrointestinal tract and lymph nodes. Therapy was given to three patients, but the disease progressed in two and they both died with evidence of central nervous system involvement, while the third patient has had a good partial response to combination chemotherapy but has relapsed within two months of completing chemotherapy. As evident from our patients and the literature review IVL has a variable clinical course and currently, there appears to be no effective therapy for this rare disorder.

Leptomeningeal metastases from solid tumors: a comparison of two prospective series treated with and without intra-cerebrospinal fluid chemotherapy.

BACKGROUND: It has been suggested that an aggressive treatment of patients with leptomeningeal metastases (LM) that groups radiotherapy and intra-cerebrospinal fluid (intra-CSF) chemotherapy has improved treatment outcomes. Based on their previous series of 137 patients treated with such an intensive standard protocol, the authors expected 20% of the patients to maintain their responses for at least 6 months after withdrawal of therapy. They also observed that, in patients with solid tumors, a partial response was compatable with sustained off-therapy response and that the maximal response was reached soon after completion of radiotherapy. The authors concluded that the role of intra-CSF chemotherapy, with its associated high rate of complications, is unclear. In this study, which was a further evaluation of this dilemma, they compared the outcomes of two prospective treatment protocols that were identical in their use of radiotherapy and systemic chemotherapy and varied only in their inclusion or exclusion of intra-CSF chemotherapy. METHODS: Adult patients with LM from systemic solid tumors were prospectively included in the treatment protocol active at the time of their diagnosis. Group 1 comprised 54 patients treated by radiotherapy, intra-CSF chemotherapy, and systemic therapy, whereas Group 2 comprised 50 patients treated with radiotherapy, and systemic chemotherapy but no intra-CSF chemotherapy. RESULTS: The analysis of treatment outcomes was performed retrospectively. The median patient age and distribution of primary neoplasms did not differ between the two groups. The proportion of early deaths that occurred during radiotherapy was similar for the two groups, as was the overall rate of response to treatment. The two groups also had the same median survival, which was 4 months for both groups, as well as the same proportion of long term survivors. Thirty-one percent of patients in Group 1 developed early complications related to intra-CSF chemotherapy, whereas patients in Group 2 were spared these complications. Delayed symptomatic leukoencephalopathy was observed in 20% of Group 1 patients compared with none in Group 2 (P = 0.02). CONCLUSIONS: The exclusion of intra-CSF chemotherapy from the treatment schedule of patients with LM does not change their overall response to treatment, their median survival, or the proportion of long term survivors. It does, however, significantly reduce the rate of early and delayed treatment-related complications.

Cisplatin-induced non-convulsive encephalopathy.

Cisplatin is a widely used chemotherapeutic agent implicated in a range of adverse effects affecting the nervous system. Among the others, convulsive encephalopathy is rare and its pathogenesis is unknown. We report an 84-year-old woman with adenocarcinoma of the ovary who developed two fully reversible episodes of non-convulsive encephalopathy, each following a course of cisplatin-based chemotherapy and thus confirming a causal relationship to the agent. The patient presented 7 and 10 days after treatment with acute confusional state, a partial left homonymous hemianopia and a left extinction hemihypesthesia. Brain MRI showed old-standing cerebral microvascular changes and EEG revealed right parieto-occipital periodic lateralized epileptiform discharges over a generalized background activity slowing. This case adds further to the clinical diversity of cisplatin toxicity and, in view of the similarity to a recently defined disorder of posterior leukoencephalopathy, suggests regional endovascular injury rather than a direct cerebral toxicity as the initial event in the evolution of encephalopathy.