Familial Dandy–Walker syndrome: a case report supporting an autosomal inheritance

Introduction We report an isolated pedigree in which a consanguineous couple had twin sons with Dandy–Walker malformation (DWM). The mother is similarly affected with the disorder.Discussion DWM is an abnormality of the central nervous system, which leads to hydrocephalus and is associated with other abnormalities.Conclusion Inheritance of the disorder remains controversial, with the majority perceived to be sporadic cases. This report suggests an autosomal inheritance.     

Characterization of an Autism-Associated Segmental Maternal Heterodisomy of the Chromosome 15q11–13 Region

Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome (PWS/AS) critical region have been described in individuals with autism. Maternal duplications and linkage disequilibrium in families with autism suggest the existence of a susceptibility locus at 15q11–q13. Here, we describe a 6-year-old girl diagnosed with autism, developmental delay, and delayed expressive and receptive language. The karyotype was designated de novo 47, XX, idic(15)(q13). Fluorescence in situ hybridization (FISH) and molecular analysis with 15q11–q13 markers revealed an additional copy of the region being of maternal origin. Duplication of the 15q11–q13 segment represents the most consistent known chromosomal abnormality reported in association with autism. This present case report reinforces the hypothesis that additional copies of this chromosome segment are causally related to autism.     

Case report: autistic disorder and chromosomal abnormality 46, XX duplication (4) p12-p13

 We report an 18-year-old female with a diagnosis of DSM-IV Autistic Disorder and moderate to severe mental retardation who was discovered to have a previously undescribed chromosomal abnormality 46, XX, duplication (4) p12–p13. We discuss her history and diagnosis, noting that the co-occurrence of her diagnoses have not previously been documented. The report adds to the literature supporting the argument that individuals with autistic spectrum disorders should be re-examined for chromosomal abnormalities. Accepted: 17 April 2000     

Irreversible striatal neuroimaging abnormalities secondary to prolonged, uncontrolled diabetes mellitus in the setting of progressive focal neurological symptoms

Hemichorea–hemiballisum in patients with hyperglycemia and striatal hyperintensity on T1-weighted magnetic resonance imaging is now an accepted clinical entity. Usually, both the clinical syndrome and neuroimaging abnormalities are reversible. A transient, reversible metabolic impairment within the basal ganglion has been considered a possible cause of this disorder. However, the pathophysiology remains to be unclear. We report a 56-year-old man with a prolonged, uncontrolled hyperglycemia (HbA1C: 13.8%) and striatal hyperintensity on T1-weighted MR imaging presenting as reversible focal neurological deficit and irreversible neuroimaging abnormalities on the fourth month when blood sugar was under control (HbA1C 6.0 mg/dl). We hypothesize that neuroimaging abnormalities in our case may be a sequence of an “ischemic insult” caused by prolonged, uncontrolled hyperglycemia. Whether the signal abnormalities on neuroimaging studies or the clinical syndrome are reversible (patients with HCHB) or irreversible (such as in our case) are based on the degree of ischemic damage.     

Neurodevelopmental and Psychiatric Symptoms in Patients with a Cyst Compressing the Cerebellum: an Ongoing Enigma

A patient diagnosed with developmental delay, intellectual disability, and autistic and obsessive-compulsive symptoms was found to have a posterior fossa arachnoid cyst (PFAC) compressing the cerebellum. The patient was referred to our Ataxia Unit for consideration of surgical drainage of the cyst to improve his clinical constellation. This scenario led to an in-depth analysis including a literature review, functional resting-state MRI analysis of our patient compared to a group of controls, and genetic testing. While it is reasonable to consider that there may be a causal relationship between PFAC and neurodevelopmental or psychiatric symptoms in some patients, there is also a nontrivial prevalence of PFAC in the asymptomatic population and a significant possibility that many PFAC are incidental findings in the context of primary cognitive or psychiatric symptoms. Our functional MRI analysis is the first to examine brain function, and to report cerebellar dysfunction, in a patient presenting with cognitive/psychiatric symptoms found to have a structural abnormality compressing the cerebellum. These neuroimaging findings are inherently limited due to their correlational nature but provide unprecedented evidence suggesting that cerebellar compression may be associated with cerebellar dysfunction. Exome gene sequencing revealed additional etiological possibilities, highlighting the complexity of this field of cerebellar clinical and scientific practice. Our findings and discussion may guide future investigations addressing an important knowledge gap—namely, is there a link between cerebellar compression (including arachnoid cysts and possibly other forms of cerebellar compression such as Chiari malformation), cerebellar dysfunction (including fMRI abnormalities reported here), and neuropsychiatric symptoms?     

Rhombencephalosynapsis and related anomalies: a neuropathological study of 40 fetal cases

Rhombencephalosynapsis is an uncommon cerebellar malformation defined by vermian agenesis with fusion of the hemispheres and of the dentate nuclei. Embryologic and genetic mechanisms are still unknown, and to date, no animal models are available. Ultrasound diagnosis is generally suspected after 22 weeks of gestation, and usually the abnormality is suggested by ventriculomegaly. Morphological analysis of 40 fetuses after medical termination of pregnancy allowed us to confirm that rhombencephalosynapsis was always associated with other brain abnormalities or malformations: Purkinje cell heterotopias, fusion of colliculi, forking and/or atresia of the aqueduct and of the third ventricle resulting in a fusion of the thalami, agenesis of the corpus callosum, lobar holoprosencephaly and neural tube defects. Pons and medulla were very infrequently abnormal. Furthermore, complete autopsy made it possible to separate either pure neurologic phenotypes, or associated with extraneural anomalies from syndromic forms: Gomez–Lopez-Hernandez syndrome (1 case) and VACTERL-H syndrome (6 cases). The number of our fetal cases strongly suggests that VACTERL-H association related with rhombencephalosynapsis emerges as a non-random association. Furthermore, recurrence and consanguinity were noted in two different families, which argue for a sporadic or inherited cause. From our results, it could be suggested that rhombencephalosynapsis may be due to defective genes regulating formation of the roof plate and the development of midline cerebellar primordium at the junction of the mesencephalon and of the first rhombomere.     

Odor abnormalities caused by bilateral thalamic infarction

Odor is the only sensation thought to be unrelated to the thalamus. However, accumulating evidence suggests that the dorsomedial nucleus (DM) of the thalamus is associated with odor. Although the thalamus is prone to ischemia, only a single patient with bilateral DM infarctions was reported to have odor abnormalities. We describe a second such patient with infarctions involving the left DM and the right ventral posterior nucleus and ventral lateral nucleus, nuclei adjacent to the DM, associated with transient edema. In contrast to the previous case, our patient had transient odor abnormality. These observations suggested that direct and/or indirect bilateral involvement of the DM might be associated with odor abnormalities in patients with thalamic infarction.     

'Agenesis' of the temporal lobe. A case report with autopsy findings.

The temporal lobe agenesis syndrome is a rare congenital abnormality. In previous case reports, this syndrome has been described in association with arachnoid cysts or abnormal collections of CSF. An autopsy performed in the case of our 25-year-old patient revealed agenesis of frontal and temporal lobes without an anatomic cyst. During life the patient had no neurologic abnormalities that could be related to the lesion.     

Alexander's disease: unique presentation.

Subacute necrotizing encephalomyelopathy (Leigh syndrome) refers to a nebulous disease entity characterized by lactic acidosis, a wide variety a clinical manifestations, and a consistent conglomeration of pathologic findings. Several abnormalities in metabolism have been delineated in association with Leigh syndrome, but many cases have no identified metabolic abnormality. We report a case that clinically, metabolically, and neuroradiologically appeared to be Leigh syndrome. In addition, our patient exhibited other unusual clinical findings, including ocular motility abnormalities. Neuropathologically, however, the diagnosis of Alexander's disease was confirmed. A review of the literature failed to find other cases of Alexander's disease reported with the metabolic abnormalities and clinical manifestations with which our patient presented.     

Neurosarcoidosis

Objective Chronic involvement of the nervous system is relatively rare in sarcoidosis. We describe 7 cases that fulfil Zajicek's criteria for neurosarcoidosis (NS) and propose some modifications to such criteria. Materials and methods The patients were admitted for various neurological syndromes: 2 cases presented with chronic lymphocytic meningitis, 4 with spinal cord symptoms, one case was initially confused with multiple sclerosis. Serological tests, immunological screening, cerebrospinal fluid (CSF) analysis, bacteriological and viral testing were performed in all patients. Spinal and cerebral MRI, gallium scan, bronchoscopy with biopsy and bronchoalveolar–lavage fluid analysis, high–resolution computed tomography (HRCT) of the chest, biopsy of the lungs, skin, mediastinal lymph–node and meninges, were useful in diagnosing NS. Results and discussion Laboratory tests showed serum inflammatory abnormalities, but were negative for infectious diseases, while CSF showed inflammatory signs in all patients. MRI revealed meningeal enhancement or hypertrophic pachymeningeal lesions in 4 patients, white matter abnormalities and mass lesions in 2 patients, and a spinal mass lesion in 1 patient. Gallium scan, HRCT, bronchoscopy were positive in most cases. Patients were treated with steroid and immunosuppressive therapy, with improvement in six cases. One patient died from infectious complications. Conclusion A definite diagnosis of NS requires demonstration of non–caseating granulomas affecting nervous tissues. In most cases, histological evidence of systemic disease (probable NS) is sufficient in the presence of compatible alterations in the CNS. In our patients the bronchoalveolarlavage fluid analysis, gallium scan, and chest HRCT were important for diagnosis,while serum ACE was always normal and chest radiographs were not suggestive of sarcoidosis.     

Asymmetric chorea as presenting symptom in Graves’ disease

Chorea is an involuntary movement disorder characterized by irregular, brief movements that flow from one body part to another in a non-stereotyped fashion. In rare instances, chorea is associated with autoimmune thyroid disease. Most of them have been related with Hashimoto’s encephalopathy and few cases have been related with Graves’ disease. Most reported cases have been in women with Graves’ disease. We describe a 16-year-old male patient with asymmetric chorea as presenting symptom in Graves’ disease. He had no family history of neurological disease. Brain imaging, laboratory findings and electroencephalogram demonstrated no abnormality except for thyroid dysfunction which was proved by thyroid function test, sonography and radioiodine uptake scan. Asymmetric chorea improved over months after anti-thyroid medications. This asymmetry could be explained by difference in increased hypersensitivity or by the difference in the number of dopamine receptors, and an asymmetrical breakdown of blood–brain barrier due to their genetic differences.     

What Can We Learn From Freezing of Gait in Parkinson’s Disease?

Freezing of gait (FOG) is defined as an episodic inability to generate effective stepping in the absence of any known cause, other than parkinsonism or high-level gait disorders. Substantial effort has been made to describe the clinical and kinematic characteristics of patients with FOG. In our review, we highlight the distinctive features of FOG in Parkinson’s disease (PD) and apply the knowledge of its pathophysiology in PD to other clinical situations and conditions. It is possible that FOG in PD represents the ultimate break in the frontal lobe–basal ganglia–cerebellar–brainstem network that controls gait. Dysrhythmic and discoordinated gait with abnormal scaling of stride length, as well as gait festination, likely is the primary and continuous abnormality of “the gait network” in PD, and FOG represents its extreme and complete but transient disruption.     

Brain malformation in syndromic craniosynostoses,a primary disorder of white matter: a review

Background Syndromic craniosynostoses (Saethre–Chotzen, Pfeiffer 1, 2, 3, Apert, Crouzon, mainly) are particular in this that a single gene defect (mostly fibroblast growth factor receptor [FGFR] 2) generates different clinical phenotypes that characterize these syndromes. Significant brain abnormalities have been reported in all syndromes. However, whether these abnormalities are secondary to the bone disease or primary (e.g. callosal agenesis) is still controversial. Recent evidence suggests that the white matter defect might be a primary disorder. Review of literature From the review of the literature and the analysis of our cases, it appears that three categories of brain abnormalities can be found. (1) The global distortion of the brain is likely mechanical and in keeping with the deformity of the skull. (2) The chronic tonsillar herniation (Chiari I deformity) is likely mechanical also and a consequence of the small size of the posterior fossa, especially after an early closure (before 24 m) of the lambdoid suture. (3) On the contrary, the constellation of abnormalities that selectively involve the white matter (non-progressive, non-destructive ventriculomegaly, callosal agenesis or thinning, agenesis of septum pellucidum, paucity of the antero-mesial temporal white matter, pyramidal hypoplasia) is much more likely to constitute a primary disorder. Conclusions Recent neurobiological evidence supports this point of view. L1 cell adhesion molecule (L1CAM) gene plays a major role in the development of the white matter and its mutation in humans (callosal agenesis, retardation, adducted thumbs, spasticity, and hydrocephalus syndrome, Bickers–Adams syndrome) or in mice causes similar defects of the corpus callosum, septum pellucidum, centrum semi-ovale, and cortico-spinal tracts. To operate, L1CAM need interactions with FGFRs, whose defects are causal to the syndromic craniosynostoses. It seems logical to assumes that the FGFR defects generate both the skull abnormalities and, by lack of interaction with L1CAM, the primary defect of the white matter. The mental deficiency that is common in these patients therefore is likely to be part of the disease (through the L1CAM–FGFR interaction) rather than a consequence of the skull size or of the associated hydrocephalus. Presented at the Consensus Conference on Pediatric Neurosurgery, Rome, 1–2 December 2006.     

“Habit” gambling behaviour caused by ischemic lesions affecting the cognitive territories of the basal ganglia

We report the case of a patient suffering from sudden apathy and pathological gambling-like behaviour after bilateral ischemic lesions involving the dorsal portion of the head of the caudate nuclei and adjacent anterior limb of the internal capsules. This is the first report of the association of an apathy and abnormal gambling behaviour following a stroke affecting sub-cortical structures. Although the location of the lesions, affecting the dorsal striatum, may explain the emergence of an apathetic state, it is, however, at first sight, not easy to explain the gambling behaviour because the patient was normal in tests evaluating sensitivity to reward, and no radiological abnormality was found in the cortical-sub-cortical system of reward. It is proposed that, for this patient, the mechanism of maladaptive gambling behaviour was the development of a routine behaviour related to the patient’s cognitive inertia, a mechanism different from the changes in reward sensitivity observed after damage to the orbital ventral prefrontal–ventral striatum system or in dopamine dysregulation syndrome in Parkinson’s disease.     

Increased EEG power density in alpha and theta bands in adult ADHD patients

This study examined EEG abnormalities in adults with attention deficit hyperactivity disorder (ADHD). We investigated EEG frequencies in 34 adults with ADHD and 34 control subjects. Two EEG readings were taken over 5 min intervals during an eyes-closed resting period with 21 electrodes placed in accordance with the international 10–20 system. Fourier transformation was performed to obtain absolute power density in delta, theta, alpha and beta frequency bands. The ADHD patients showed a significant increase of absolute power density in alpha and theta bands. No differences were found for beta activity. Our findings indicate that abnormalities in the EEG power spectrum of adults with ADHD are different than those described in children. Reliable discriminators between patients and healthy subjects in adulthood could be alpha and theta power density. Based on our results, we suggest further research involving longitudinal studies in ADHD patients to investigate the changes of EEG abnormalities with age.     

Prolonged refractory status epilepticus with early and persistent restricted hippocampal signal MRI abnormality

We report a series of four children with a prolonged refractory status epilepticus with an early persistent and restricted hippocampal signal MRI abnormality but otherwise no proven etiology. The mean duration of status epilepticus was 53 days (range, 20–91 days) with a mean length of stay in Pediatric Intensive Care Unit (PICU) of 2 months (range, 26–115 days). Neurological outcome showed epilepsy disease in all, and mild to severe disability. In long-term follow-up, the initial MRI signal abnormality developed into a cortical atrophy in all cases. The establishment of the diagnosis, etiology, and options for treatment are discussed.     

A new POLG1 mutation with peo and severe axonal and demyelinating sensory–motor neuropathy

Background Progressive external ophthalmoplegia (PEO) is a mitochondrial disorder associated with defective enzymatic activities of oxidative phosphorylation (OXPHOS), depletion of mitochondrial DNA (mtDNA) and/or accumulation of mtDNA mutations and deletions. Recent positional cloning studies have linked the disease to four different chromosomal loci. Mutations in POLG1 are a frequent cause of this disorder. Methods We describe two first–cousins: the propositus presented with PEO,mitochondrial myopathy and neuropathy, whereas his cousin showed a Charcot– Marie–Tooth phenotype. Neurophysiological studies, peroneal muscle and sural nerve biopsies, and molecular studies of mtDNA maintenance genes (ANT1, Twinkle, POLG1, TP) and non dominant CMT–related genes (GDAP1, LMNA, GJB1) were performed. Results A severe axonal degeneration was found in both patients whereas hypomyelination was observed only in the patient with PEO whose muscle biopsy specimen also showed defective OXPHOS and multiple mtDNA deletions. While no pathogenetic mutations in GDAP1, LMNA, and GJB1 were found, we identified a novel homozygous POLG1 mutation (G763R) in the PEO patient. The mutation was heterozygous in his healthy relatives and in his affected cousin. Conclusions A homozygous POLG1 mutation might explain PEO with mitochondrial abnormalities in skeletal muscle in our propositus, and it might have aggravated his axonal and hypomyelinating sensory–motor neuropathy. Most likely, his cousin had an axonal polyneuropathy with CMT phenotype of still unknown etiology.     

Hemimegalencephaly: a fetal case with neuropathological confirmation and review of the literature

Hemimegalencephaly (HME) is a developmental abnormality of the central nervous system, identified by an abnormal increase in the size of one cerebral hemisphere. HME may present as either a syndromic or isolated case. To date the literature on HME has focused primarily on non-fetal pediatric patients, largely related to surgical resection specimens of the HME hemisphere. We present the case of a male fetus at 22 weeks gestation with intracranial abnormalities identified on a follow-up ultrasound. Gross examination of the fetal brain confirmed the increased size of the right cerebral hemisphere. The ipsilateral brain stem and cerebellum were not involved. Light microscopy demonstrated the presence of accelerated cortical differentiation along with several migrational anomalies in the HME hemisphere. Based on the gross and microscopic findings, a diagnosis of fetal hemimegalencephaly was made. The periventricular proliferative zone of the abnormal hemisphere contained a normal population of neuroepithelial precursor cells. An exhaustive immunohistochemical study found immunoreactivity for calretinin and synaptophysin, while the Ki-67 proliferation labeling was not increased in the HME hemisphere. Our case is the first autopsied report on fetal hemimegalencephaly and confirms that the key pathogenic changes may present as early as 20–22 weeks gestation. The major pathological features of our case are in keeping with a disturbance in accelerated neuronal differentiation and migrational abnormalities.     

Increasing use of intravenous rt–PA does not affect safety in acute stroke

Background Intravenous thrombolysis with rt–PA improves outcome in acute ischemic stroke. In a prospective study we analyzed the annual frequency of rt–PA treatment, its safety, and early clinical outcome. Methods All patients admitted to our stroke unit (SU) from 1998 to 2003 were registered in a prospective data base. Documented data included patient age, sex, time interval until admission, initial therapy (e. g., thrombolysis), death, intracerebral hemorrhage, other complications, and score on the National Institute of Health Stroke Scale (NIHSS). Results From 1998 to 2003, a total of 112 patients were treated with systemic thrombolysis. The number of acute stroke patients admitted within 2.5 hours and therefore eligible for thrombolysis did not substantially change between 1998 and 2003. From 1998 to 2001 the percentage of acute stroke patients that received rt–PA was stable (12.6–16.9 %). This percentage increased in 2002 (29.6%, p<0.05) and, again, in 2003 (42.1%, p<0.01). Of all treated patients, two developed symptomatic intracerebral hemorrhage (1.8%) and five died three to seven days after thrombolysis (4.5 %). The NIHSS score of patients receiving rt–PA significantly decreased during the acute treatment phase (14.2±5.1 to 8.0±5.9, p<0.001). A comparison of single years revealed that this NIHSS score reduction was stable. Conclusion In our selected patients, the proportion of acute stroke patients treated with systemic thrombolysis increased almost three–fold from 1998 to 2003. This may be explained by protocol modifications and growing experience with the use of rt–PA. Our data demonstrate that increased use of rt–PA in acute stroke patients can be achieved without adversely affecting safety or clinical benefit.