Michael T. Richard

Subtle Neuropsychological Deficits in Patients with Good Recovery after Closed Head Injury

This study demonstrates residual mental deficits in patients who have apparently recovered after closed head injury. Twenty closed head injury patients were compared to 20 normal control subjects matched for age, sex, handedness, education, language, and IQ. All received a series of neuropsychological tests. Discriminant function analysis significantly differentiated the two groups. Correct classification of individuals as having suffered a head injury or not was 85%. The head injury patients did have primary impairment on tests of divided attention. Litigation was not a factor. We propose that this impairment of information processing reflects residual brain damage secondary to the closed head injury.

How long does it take to recover from a mild concussion

&NA; Twenty‐two adults with mild concussions were assessed 5 times during the first 3 months after injury. The initial tests were performed within 72 hours of injury. Each evaluation included a neurological examination and neuropsychological reaction time (RT) tests of simple and choice RT variations. The concussed subjects were compared with control subjects matched for age, sex, and education. The time of day of the testing was equated for the two groups. None of the concussed subjects had a significant neurological deficit and none was hospitalized. There was no significant difference in the number of errors by the two groups on the RT tests. On the simple RT test, requiring a predetermined response to a specific signal, there was no significant difference between the groups, although the concussed group was approximately 28 ms slower on the average than the control group. On the choice RT tests, however, which demand an increased amount of attention and information processing, the concussed subjects were significantly slower than the normal control group, especially during the 1st month after injury. Even after 3 months, the concussed subjects had not yet attained the skill of the control group. Analysis of the response curves over time suggested two processes: an improvement in the concussed group and a slowing in the control group. Within the concussed group, there was no correlation of RT with the severity of the concussion. Even mild concussions can cause significant attentional and information processing impairment in the absence of any apparent neurological problems. Specific neuropsychological tests are necessary to reveal the deficit. A significant impairment seems to last for several weeks. There is a gradual improvement over 3 months, suggesting a recovery process.

Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm

Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.

Chronic cerebrovascular insufficiency induces dementia-like deficits in aged rats

Young and aged rats were subjected to cerebrovascular insufficiency (CVI) for 3 and 9 weeks. At the end of each time period, local cerebral blood flow (lCBF), spatial memory function, 31P- and 1H-NMR spectroscopy and imaging of the brains were evaluated in vivo. Morphometric counts of CA1 hippocampal neuron damage and staining for glial fibrillary acidic protein (GFAP) were done post-mortem. Results show that after 3 weeks of CVI, cortical and hippocampal lCBF was significantly reduced in young and aged animals respectively. In addition, young and aged rats at 3 weeks following CVI showed spatial memory deficits in the Morris water maze and elevation of 31P-phosphomonoester as measured by non-invasive NMR spectroscopy. At the same time period, in vivo 1H-microimaging (MRI) of brains showed areas of high signal intensity (suggesting local edema) localized asymmetrically to the right hippocampal region in young and aged CVI rats. Morphometry of the hippocampal CA1 sector at post-mortem confirmed the in vivo MRI changes and demonstrated that a significant percentage of the CA1 pyramidal cells were damaged after CVI. Nine weeks after CVI, hippocampal CBF reductions, spatial memory impairment, spectroscopic-microimaging changes and CA1 sector cell damage continued to be observed in the aged animals but were resolved in the young rat brains. In addition, GFAP immunoreaction progressively increased in the hippocampus of aged rats subjected to CVI for 9 weeks. It is concluded that cognitive, metabolic and morphologic damage was significantly more severe and longer lasting in aged than young rat brain after chronic CVI. The deficits observed in this rat model appear to mimic the early pathology reported in Alzheimers disease and suggest that the present model could provide fundamental clues relative to the etiology and possible management of this dementia.

Penetration of VP-16 (etoposide) into human intracerebral and extracerebral tumors

SummaryVP-16 100 mg/m2 was given intravenously to 10 patients undergoing surgical resection of intracerebral tumors, and the drug was assayed in resected tumor using high pressure liquid chromatography. VP-16 concentrations varied from undetectable (<.1 µg/g) to 5.9 µg/g (mean, 1.4 µg/g). VP-16 concentrations in tumors were lower than concurrent plasma concentrations. In addition, intracerebral tumors had a lower concentration of VP-16 than did extracerebral tumors (mean VP-16 concentration, 3.9 µg/g) from 7 patients receiving VP-16 50–100 mg/m2 intravenously. Plasma pharmacokinetics of VP-16 were different in our patients with intracerebral tumors than in previously studied patients with extracerebral tumors and it is unclear what role this may have played invariability of tumor VP-16 concentrations. VP-16 concentrations were similar in glioblastomas and brain metastases. Specimens from patients with small cell undifferentiated carcinoma of the lung had the highest VP-16 concentrations. A patient who had both viable and necrotic tumor resected during an occipital lobectomy had a higher drug concentration in the necrotic than in the viable area of tumor. In addition, VP-16 concentration decreased as a function of distance into brain from the tumor. Based on our data, VP-16 might be expected to have less activity against intracerebral than against extracerebral human tumors.

Spontaneous dissecting aneurysm of the extracranial vertebral artery.

Spontaneous dissection of a cervical vertebral artery secondary to fibromuscular hyperplasia is uncommon, is often painful, and may be followed after a latent interval by further symptoms of embolism, occlusion, or hemorrhage. Accordingly, the lesion is potentially hazardous and warrants treatment when recognized.

Intracarotid Chemotherapy with a Combination of 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU), cis-Diaminedichloroplatinum (Cisplatin), and 4'-O-Demethyl-1-O-(4,6-O-2-thenylidene-β-D-glucopyranosyl)epipodophyllotoxin (VM-26) in the Treatment of Primary and Metastatic Brain Tumors

Thirty-seven patients with intracranial primary or metastatic tumors were treated with an intraarterial combination of BCNU, cisplatin, and VM-26 to determine the efficacy, toxicity, and maximal tolerated doses for the combination. A transfemoral fluoroscopic approach was used to catheterize temporarily the internal carotid or vertebral artery. Thirteen of 19 (68%) evaluable primary brain tumors and 9 of 16 (56%) evaluable brain metastases responded. The response rate was lower in patients previously treated with both cranial irradiation and i.v. chemotherapy than in patients less heavily pretreated (54% vs. 82%), although even patients previously treated i.v. with all three of the study drugs responded. All five patients with both extracranial and intracranial evaluable tumor deposits experienced a greater response of their intracranial than of their extracranial tumor. Ipsilateral retinal and neurological toxicity were dose-limiting, with major toxicity (permanent decreased vision or hemiparesis) occurring in five of nine (56%) patients receiving doses of BCNU greater than or equal to 100 mg/m2 plus cisplatin, 60 mg/m2 plus cisplatin, 60 mg/m2, plus VM-26, 175 mg/m2. Only 9% of the patients treated with a lower VM-26 dose developed permanent severe toxicity, and the doses that we now recommend are: BCNU, 100 mg/m2; cisplatin, 60 mg/m2; and VM-26, 150 mg/m2. The response rate was also dose-related (100% at the highest doses tested vs. 57% at the lower doses).(ABSTRACT TRUNCATED AT 250 WORDS)

Human central nervous system and plasma pharmacology of mitoxantrone

Mitoxantrone 5–6 mg/m2 was administered IV to 10 consenting patients prior to surgical resection of an intracerebral tumor. Plasma pharmacokinetic parameters were calculated and concentration of mitoxantrone in intracerebral tumors was determined. Concentrations of mitoxantrone were also determined in autopsy tissues of one of the patients who expired 192 days after receiving the drug. The plasma pharmacokinetics were best described by a 3 compartment model, with a t1/2γ of 4.74±5.53 h. Mitoxantrone concentrations in the intracerebral tumors were potentially cytotoxic and ranged from 4 to 322 ng/g. In all but one case, mitoxantrone concentration was higher in tumor than in concurrent plasma samples. There was no obvious relation between tumor mitoxantrone concentration and peak plasma mitoxantrone concentration or time from mitoxantrone administration to tumor removal. Low grade gliomas and viable tumors tended to have lower mitoxantrone concentrations than did other tumor types and necrotic tumors. In the patient undergoing autopsy, highest mitoxantrone concentrations were found in liver, thyroid and heart.

Toxocara canis infestation with encephalitis.

The syndrome “visceral larva migrans” produced by migration of nematode larvae (commonly Toxocara species) in the extraintestinal tissues in unusual hosts, including man (particularly children of dirt eating age), with the production of reactive granulomatous lesions, was first described in 1952. About 200 cases have been reported since. Well documented cases are rare due to the difficulty in histological verification. Three cases have been reported in Canada but these were not verified. We believe the present report is the first verified case of visceral larva migrans in Canada and the fifth case of human cerebral involvement by Toxocara in the English literature. It is hoped that this report will emphasize the need for further research into the role of host versus parasite and will underline the potential danger, albeit remote, of household pets to children. Indeed, prevention is the only line of attack, as there is no effective drug against the migrating larvae of Toxocara.

Cisplatin plus cytosine arabinoside in adults with malignant gliomas

SummaryA combination of cisplatin and cytosine arabinoside was used to treat 21 patients with glioblastomas and 5 patients with recurrent grade 11 gliomas. Cisplatin 60–100 mg/m2 was given I.V. in 250 ml 0.45% saline and preceded by 500 ml dextrose 5% in 0.45% saline. Mannitol 50 g was given I.V. concurrently with the cisplatin. Cytosine arabinoside 500–1000 mg/m2 was given by rapid I.V. infusion immediately after the cisplatin. Of 25 evaluable patients, 10 (40%) experienced objective tumor shrinkage on CT scan, and 6 (24%) stabilized. There were 2 complete remissions. Patients who had had no prior treatment had a higher response rate (58%) than those previously treated (23%). Myelosuppression occurred in some patients 2–3 weeks after treatment. Gastrointestinal toxicity (vomiting and diarrhea) was dose-limiting. Two patients had possible neurological toxicity. Recommended doses for further studies are cisplatin 90 mg/m2 and cytosine arabinoside 900 mg/m2.