BACKGROUND:Gamma-Knife radiosurgery can be the treatment of choice for small cerebral arteriovenous malformations (AVMs) in eloquent brain areas or, in association with endovascular treatment, for large and complex AVMs. Among the possible delayed complications occurring after radiosurgery of AVMs, de novo formation of a cavernoma has only recently been described. The authors report a unique case of communicating hydrocephalus with highly proteinaceous cerebrospinal fluid due to a cavernoma-like lesion of an obliterated cerebral AVM treated by embolization and radiosurgery.CASE DESCRIPTION:A 43-year-old female patient with a left parieto-occipital AVM (Spetzler-Martin grade III) underwent a multimodality treatment comprising several endovascular procedures and Gamma-Knife radiosurgery. At the follow-up angiograms, the AVM was completely obliterated. Twelve years later, she came back to our attention for headache and vomit with the radiological evidence of brain edema, severe hydrocephalus, and a chronic encapsulated intracerebral hematoma. At the beginning, the drainage of hydrocephalus proved ineffective to improve symptoms and edema. Therefore, the surgical resection of both the obliterated AVM and the cavernoma-like lesion-histologically confirmed-was necessary. The hydrocephalus resolved as well as the cerebral edema after 3 weeks, without necessity of a ventriculoperitoneal shunt.CONCLUSIONS:In previous neurosurgical literature, the association of a caveroma-like lesion in an obliterated AVM and communicating hydrocephalus with highly proteinaceous cerebrospinal fluid has not yet been discussed. We believe that only the surgical resection of both the obliterated AVM and the cavernoma-like lesion can lead to complete clinical recovery of the hydrocephalus.

Several mutations in various domains of the LRRK2 (leucine-rich repeat kinase 2) gene have been reported in association with familial but also apparently sporadic cases of Parkinson’s disease (PD) [1,2]. Patients with mutations in LRRK2 generally have a uniform clinical phenotype with slowly progressive, lateonset and levodopa-responsive Parkinsonism. Remarkably, they display highly variable neuropathology, with the common denominator of neuronal loss in the substantia nigra (SN) that only in a subset of cases is associated with the presence of the hallmark of PD (i.e. Lewy bodies). Here we report the clinicopathological findings in a patient with the LRRK2-G2019S mutation and an atypical tauopathy. A 72-year-old man had an onset of resting tremor in the right limbs and micrographia. The patient underwent brain SPECT (Single Photon Emission Computerized Tomography) with I-123 Ioflupane (Figure 1B), which showed significant decrease in striatal uptake with greater impairment in putamen compared to caudate nucleus; brain magnetic resonance imaging was unremarkable. The patient was initially treated with pergolide, while levodopa was added 2 years from disease onset at an initial dosage of 400 mg daily, which was gradually increased to 1000 mg daily in the following 7 years, with minimal improvement of symptoms. Bradykinesia and tremor gradually progressed and spread to the contra lateral limbs, and occasional freezing of gait appeared. Nine years from disease onset, the UPDRS (Unified Parkinson Disease Rating Scale) [3] motor score was 20/108 and remained unmodified after acute levodopa challenge, reflecting a rather mild disease but no visible improvement of motor symptoms taking levodopa after a 12-h withdrawal period, which is known as ‘short-term response’ and would instead be expected in typical PD. Cognitive impairment appeared as shown by a Mini-Mental State Examination of 23/30 (with normal scores in Frontal Assessment Battery – FAB, Clock Drawing Test – CDT, shortand long-term verbal memory) with only minor limitations in activities of daily living until the 11th year from disease onset, when postural instability worsened and depression appeared. The patient died 12 years from disease onset. He notably never developed dyskinesias or other symptoms of long-term levodopa syndrome. We screened the patient for the LRRK2-G2019S mutation (see Goldwurm et al. [4]: patient 07), which was present in the heterozygous state. MAPT haplotype analysis revealed H1/H1 homozygosity [5]. Macroscopic examination of the brain revealed severe depigmentation of the SN and no other remarkable findings. The following regions were sampled for further microscopic investigation: medulla oblongata, pons, midbrain, cerebellum, hippocampal formation, amygdala, gyrus cinguli, temporal cortex, insular cortex, caudate nucleus, putamen and globus pallidus. On all sampled blocks, routine staining with haematoxylin-eosin and Kluver Barrera as well as immunohistochemistry with the following antibodies were carried out: a polyclonal anti-tau antibody (1:500; DakoCytomation, Glostrup, Denmark); a monoclonal antibody to phosphorylated tau (AT8, monoclonal, 1:300, epitope at residues 199-205; Innogenetics, Gent, Belgium); two monoclonal antibodies that distinguish with complete specificity the tau isoforms with three (RD3, 1:1000, clone 8E6/C11; Chemicon, Temecula, CA, USA) or four microtubule-binding repeat domains (RD4, 1:300, clone 1E1/A6; Chemicon); a monoclonal antibody to Ab (4G8, 1:5000; Signet, Dedham, MA, USA); a monoclonal antibody to a-synuclein (4D6, 1:5000; Signet); a polyclonal antibody to glial fibrillary acidic protein (1:800; DakoCytomation). Neuronal loss and gliosis were moderate in the SN and appeared more severe in the ventral compared to the dorsal region. Significant neuronal loss was not detected in other brain regions. Lewy bodies, Lewy neurites or a-synuclein-immunoreactive changes were absent in all the brain regions examined. There was deposition of tau protein with lesion morphology and distribution reminiscent of progressive supranuclear palsy (PSP), although in our patient tauopathy

Aquaporin-4 (AQP4), the prominent water channel in the brain, is particularly concentrated in astrocytic endfeet membranes lining the capillaries and the pia. This localisation pattern makes it well suited to regulate the flow of water and the homeostasis of the interstitial fluid surrounding the neurons. Using immunocytochemical and Western blot techniques, we investigated the expression of AQP4 and some related proteins (i.e. glial fibrillary acidic protein, glial glutamate transporter 1, the endothelial marker CD34, and dystrophin) in tissue taken from epileptic patients. To this end, we used surgical samples containing focal cortical dysplasia (FCD) Type IIB, samples of normal-appearing (cryptogenic) cortex, and samples from non-epileptic patients as controls. AQP4 expression and distribution in the cryptogenic patients were similar to those observed in the control cases, mainly concentrated around blood vessels. In the patients with FCD type IIB, severe malformation in cortical development, the protein was more expressed and the distribution pattern of AQP4 immunoreactivity was different, being strong in the neuropil and around several dysplastic neurons, whereas the vessels appeared to be less intensely stained by AQP4 and dystrophin. As the efficiency of AQP4 in regulating water and ion homeostasis in extracellular space depends on its spatial distribution in astrocytes, the different distribution of AQP4 protein in the FCD type IIB samples may modify fluid homeostasis control and the regular functioning of neuronal cells.

Objective: To define distinctive features of nodular heterotopia in specimens derived from drug-resistant patients with epilepsy by evaluating mRNA expression of three different layer-specific markers: Rorβ, Er81, and Nurr1. Methods: We analyzed the expression profile of these genes, recognized as markers mainly expressed in layer IV for Rorβ, in layer V for Er81, and in layer VI for Nurr1, in surgical samples from 14 epileptic patients, using in situ hybridization. Six patients had subcortical nodular heterotopia and 8 patients were controls. The intrinsic organization of nodular formations and of the overlaying neocortex was assessed. Results: In all patients, the 3 selected genes showed high cortical laminar specificity. In subcortical nodular heterotopia, the different gene expression profiles revealed a rudimentary laminar organization of the nodules. In the overlaying cortex, fewer cells expressed the 3 genes in the appropriate specific layer as compared to controls. Conclusions: These data provide new insights into possible ontogenetic mechanisms of nodular heterotopia formation and show the potential role of layer-specific markers to elucidate the neuropathology of malformations of cortical development.

Intraoperative [ 111 In]-pentetreotide scintigraphy with a hand-held gamma detector probe has recently been proposed to increase the intraoperative detection rate of small neuroendocrine tumors and their metastases. We report a case of a 28-yr-old woman with ectopic Cushing’s syndrome due to an ACTH-secreting bronchial carcinoid, in whom the use of radioguided surgery improved disease management. At presentation, radiolabeled pentetreotide scintigraphy was the only procedure able to detect the ectopic source of ACTH. After radiologic confirmation, the patient underwent removal of a bronchial carcinoid, with disease persistence. After surgery, pentetreotide scintigraphy showed pathologic uptake in the mediastinum not previously detected at surgery and only subsequently confirmed by radiologic studies. Despite a second thoracic exploration, hormonal, scintigraphic, and radiological evidence of residual disease persisted. Radioguided surgery was then performed using a hand-held gamma probe 48 h after iv administration of a tracer dose of radiolabeled [ 111 In-DTPA-D-Phe1]-pentetreotide, which permitted detection and removal of multiple residual mediastinal lymph node metastases. Clinical and radiologic cure, with no evidence of tracer uptake at pentetreotide scintigraphy, was subsequently observed. The use of an intraoperative gamma counter appears a promising procedure in the management of metastatic ACTH-secreting bronchial carcinoids.

CIDP can occur with other systemic diseases such as diabetes mellitus (CIDP‐DM) and non‐malignant monoclonal gammopathy (CIDP‐MGUS). Whether I‐CIDP, CIDP‐DM and CIDP‐MGUS differ in clinical presentation, response to treatment and long‐term outcome is unclear, as well as the relationship of these concurrent diseases to CIDP. Eight patients with I‐CIDP, 16 patients with CIDP‐DM and 7 patients with CIDP‐MGUS were included in this study and sural nerve biopsies were taken. Clinical conditions were evaluated using a Neurologic Disability Scale (NDS) and a modified Rankin Scale (MRS). All patients were treated with at least 1 course of intravenous immunoglobulins (IVIg) at a dosage of 2 g/Kg administered over 5 days and classified as treatment responders or non responders according to clinical improvement. Improvement was defined as a decrease of 4 points in the NDS score. Patients were retreated in case of relapses. Relapse was defined as worsening after improvement with an increase of 4 points or more in NDS score. Sural nerve pathology was assessed on semithin sections. No differences were detected among the three groups according to age and sex. On neurologic examination the CIDP‐DM group had a significantly more severe disease based on the NDS and MRS score. In all the three groups there was an improvement after treatment but this is statistically significant only in the CIDP‐DM group. At the end of the follow‐up there is no difference in clinical conditions among the three groups but there is a significant difference according to the number of IVIg administrations and thus with the number of relapses. In conclusion CIDP‐DM is a more severe disease compared to the other 2 groups, but with a significant better response to IVIg and less number of relapses.

We present the results of a retrospective study on 10 patients operated on for intractable epilepsy associated with nodular heterotopia as identified by high resolution MRI. Seven patients had unilateral heterotopia, one patient had symmetric bilateral heterotopia and two patients had asymmetric bilateral heterotopia. By stereo-electroencephalogram (SEEG) (nine patients) interictal activity within nodules was similar in all cases, and ictal activity never started from nodules alone but from the overlying cortex or simultaneously in nodules and cortex. Excellent outcomes (Engel class Ia, 1987) were achieved in the seven patients with unilateral heterotopia, showing that surgery can be highly beneficial in such cases when the epileptogenic zone is carefully located prior to surgery by MRI and particularly SEEG. For the bilateral cases surgical outcomes were Engel IIa (one patient) or Engel IIIa (two patients). Histological/immunohistochemical studies of resected specimens showed that all nodules had similar microscopic organization, even though their extent and location varied markedly. The overlying cortex was dysplastic in nine patients, but of normal thickness. We suggest that nodule formation may be the result of a dual mechanism: (i) failure of a stop signal in the germinal periventricular region leading to cell overproduction; and (ii) early transformation of radial glial cells into astrocytes resulting in defective neuronal migration. The intrinsic interictal epileptiform activity of nodules may be due to an impaired intranodular GABAergic system.

Malformations of cortical development may be associated with drug-resistant partial epilepsy suitable for surgical therapy. From the anatomopathological point of view, this categorisation has been used in reference to a wide range of alterations of the cortical mantle. Focal cortical dysplasias represent the main group of malformations of cortical development, but there are also other types of alterations, such as heterotopias, double cortex or polymicrogyria. Defining candidacy for surgical therapy and tailored resection requires thorough pre-surgical evaluation so that the approach will be individualised for each patient. We present our series of 126 patients with malformation of cortical development selected from 321 consecutively operated patients. Within this group encompassing different types of malformation of cortical development, including periventricular heterotopia (nine patients), polymicrogyria (three patients), hemimegalencephaly (one patient) and subcortical band heterotopia (one patient), the largest group was 81 individuals with focal cortical dysplasia. For this last group, we propose a simplified classification defining 42 architectural dysplasias, 12 cytoarchitectural dysplasias and 27 Taylor's focal cortical dysplasias. In addition, at routine neuropathological investigation, the only morphological alteration shown by 31 patients was diffuse neuronal heterotopia. All patients underwent scalp EEG and video-EEG, and 75 patients (59.5%) also underwent stereo-EEG. Magnetic resonance imaging and stereotactic stereoscopic angiography represented the indispensable premises for further studies, in particular stereo-EEG, and for planning surgery and tailoring resection. Magnetic resonance imaging was unhelpful in 17 out of 81 patients with focal cortical dysplasia and in seven out of 31 with neuronal heterotopia, while signal alterations were present in all other cases. Common characteristics corresponding to clinical-histopathological homogeneous subgroups were found within the focal cortical dysplasia group. In patients with architectural dysplasia, the epileptogenic zone was mainly in the temporal lobe and there was a lower seizure frequency than in patients with Taylor's focal cortical dysplasia. Patients with Taylor's type had an epileptogenic zone that was mainly extra-temporal, and a distinctive interictal stereo-EEG. The best outcome was observed in patients with Taylor's type dysplasia: 69% seizure-free (Engel class Ia) after at least 1 year of follow-up, compared with 45% of cytoarchitectural dysplasia and 49% of architectural dysplasia patients.

Since the original description by Taylor, the term focal cortical dysplasia has been used to refer to a wide range of alterations of the cortical mantle. More recently, these conditions have been described from neuroimaging, neuropathological and genetic standpoints, generating several classifications. It is widely recognized that these classifications are unsatisfactory. We propose a simplified classification of focal cortical dysplasias based on easily recognized neuropathological characteristics. We retrospectively re-examined histological sections of cortex from 52 of 224 (23%) patients operated on for drug-resistant partial epilepsy in which cortical dysplasia was present but not associated with other brain pathologies except hippocampal sclerosis. Three subgroups were identified: (i) architectural dysplasia (31 patients) characterized by abnormal cortical lamination and ectopic neurones in white matter; (ii) cytoarchitectural dysplasia (six patients) characterized by giant neurofilament-enriched neurones in addition to altered cortical lamination; and (iii) Taylor-type cortical dysplasia (15 patients) with giant dysmorphic neurones and balloon cells (all but two patients) associated with cortical laminar disruption. The patients with architectural dysplasia had lower seizure frequency than those with cytoarchitectural and Taylor-type dysplasia, and the epileptogenic zone was mainly in the temporal lobe. In patients with Taylor-type dysplasia, the epileptogenic zone was mainly extratemporal, and interictal stereo-EEG was distinctive. MRI was unrevealing in 34% of patients, but distinctive signal alterations characterized most patients with Taylor-type dysplasia, while focal hypoplasia with MRI abnormalities was found in architectural dysplasia. Patients with Taylor-type dysplasia had the best outcome, with 75% seizure-free (Engel class Ia) after at least a year of follow-up compared with 50% of cytoarchitectural dysplasia and 43% of architectural dysplasia patients seizure-free. This three-category classification is based on easily recognized histopathological characteristics and avoids complicated terminology, while the distinctive ensemble of other characteristics defines clinically homogeneous groups.

Cajal-Retzius cells, identified using calretinin antiserum, were studied in layer I (LI) of adult human temporal cortex from epileptic patients with Taylor's focal cortical dysplasia and architectural dysplasia, in comparison with normal cortex. Both types of dysplasia showed LI hypercellularity, but only in architectural dysplasia was the density of Cajal-Retzius cells significantly increased. A subset of Cajal-Retzius cells were reelin immunoreactive, but none were GABA positive. These findings suggest that differences in the persistence of Cajal-Retzius cells, which probably reflect different types of alteration during brain development, can assist in characterizing different forms of cortical dysplasia.

Forty consecutive patients with chronic sensorimotor polyneuropathy of undetermined cause were followed to determine disease progression and prognosis. They had had neurological symptoms for at least 1 year before presentation. Neurophysiological examination in all patients showed chronic axonal degeneration, which was confirmed by sural nerve biopsy. Patients were reviewed every 3 months. Laboratory tests were performed every 6 months for the first 2 years and then annually. Neurophysiological examination was performed annually in all patients. Patients were followed up for at least 4 years. In no instance was a possible etiological factor detected during follow‐up. The clinical and electrophysiological findings had a slowly progressive course. We suggest that patients with a chronic polyneuropathy of undetermined cause despite detailed investigations do not require further extensive and expensive laboratory tests and neurophysiological studies during follow‐up. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 1197–1201, 2001