Gerard Hageman

Parkinsonism, pyramidal signs, polyneuropathy, and cognitive decline after long-term occupational solvent exposure.

Abstract It is well known that exposure to manganese, solvents, or carbon monoxide in an occupational setting may lead to central nervous system damage and parkinsonism. The most important solvents in this respect are methanol, toluene, carbon disulfide, and n-hexane. We describe three patients who had been exposed to various solvents for more than 20 years (25, 34, and 46 years). They presented with parkinsonism, pyramidal signs, mild cognitive decline, and unresponsiveness to levodopa. Two patients had a predominantly axonal and sensory polyneuropathy of the lower legs with fasciculations in one of them. Parkinsonian features were progressive, even after the patients had stopped work. We present clinical data, neuropsychological findings, and results of brain computed tomography or magnetic resonance imaging, electroneuromyography, evoked potentials, single photon emission computed tomography, and positron-emission tomography. There is growing evidence that various organic solvents give rise to a parkinsonism syndrome with pyramidal features in susceptible individuals.

Suboptimal performance on neuropsychological tests in patients with suspected chronic toxic encephalopathy.

Suboptimal performance during neuropsychological testing can seriously complicate assessment in behavioral neurotoxicology. We present data on the prevalence of suboptimal performance in a group of Dutch patients with suspected chronic toxic encephalopathy (CTE) after long-term occupational exposure to solvents. One hundred and forty-five subjects referred to one of two Dutch national assessment centers for CTE were administered the Amsterdam Short-Term Memory Test (ASTM) and the Test of Memory Malingering (TOMM), two tests specifically developed for the detection of suboptimal performance. For both tests, very cautious cut-off scores were chosen with a specificity of 99%. Results indicated that suboptimal performance appears to be a substantial problem in this group of patients with suspected CTE after long-term exposure to organic solvents. Only 54% of our subjects obtained normal scores on both tests of malingering, i.e. at or above cut-off score. The two tests seemed to measure the same concept in that nearly all the subjects with low TOMM scores also had low ASTM scores. However, a higher proportion of subjects scored below the cut-off on the ASTM than on the TOMM.

Dandy-Walker complex in a boy with a 5 Mb deletion of region 1q44 due to a paternal t(1;20)(q44;q13.33).

A 10‐year‐old boy with vermis hypoplasia, dilatation of the fourth ventricle, enlarged cisterna magna and aplasia of the corpus callosum, consistent with the Dandy‐Walker complex (DWC), and slight facial dysmorphisms, severe motor and mental retardation is presented. By combining data obtained by karyotyping, array‐CGH, FISH, and multiplex ligation‐mediated probe amplification (MLPA) we identified a 5 Mb deletion of the 1q44 → qter region resulting from a paternal t(1;20)(q44;q13.33). This smallest 1q44 deletion reported so far, enabled us to significantly narrow down the number of candidate genes for the DWC in this region. Since the ZNF124 transcription factor is strongly expressed in the fetal brain it may represent a candidate gene for the DWC at 1q44.

Routine diagnostic procedures for chronic encephalopathy induced by solvents: survey of experts

OBJECTIVES To study the routine diagnostic procedures used in different countries for chronic toxic encephalopathy (CTE) induced by solvents. METHODS By means of a postal questionnaire selected international experts were asked about the methods they use to diagnose patients suspected of having CTE induced by solvents, the number of patients, entrance criteria, and the results of these diagnostic procedures. RESULTS 18 Experts working in 18 diagnostic centres responded. Most of them agreed that a diagnostic procedure for CTE induced by solvents should contain an interview and neurological, physical, and neuropsychological examinations. However, the tests used were very different, as were the classifications for CTE. Depending on the institute, a diagnosis of CTE was made in 6%–70% of the referred patients. The proportion of patients with CTE stage I ranged from 0% to 33%, stage II from 5% to 100%, and stage III from 0% to 95%. CONCLUSION The intentions of the two 1985 conferences that aimed at clarity and uniformity of diagnosis of CTE induced by solvents are far from reached. It is possible, now the conditions are more favourable, to aim at this important goal and recommend some refinement of the then proposed criteria.

Refinement of the chromosome 16 locus for benign familial infantile convulsions

Benign familial infantile convulsions (BFIC) is an autosomal dominantly inherited partial epilepsy syndrome of early childhood with remission before the age of 3 years. The syndrome has been linked to loci on chromosomes 1q23, 2q24, 16p12‐q12, and 19q in various families. The aim of this study was to identify the responsible locus in four unrelated Dutch families with BFIC. Two of the tested families had pure BFIC; in one family, affected individuals had BFIC followed by paroxysmal kinesigenic dyskinesias at later age, and in one family, BFIC was accompanied by later‐onset focal epilepsy in older generations. Linkage analysis was performed for the known loci on chromosomes 1q23, 2q24, 16p12‐q12, and 19q. The two families with pure BFIC were linked to chromosome 16p12‐q12. Using recombinants from these and other published families, the chromosome 16‐candidate gene region was reduced from 21.4 Mb (4.3 cm) to 2.7 Mb (0.0 cm). For the other two families, linkage to any of the known loci was unlikely. In conclusion, we confirm the linkage of pure BFIC to chromosome 16p12‐q12, with further refinement of the locus. Furthermore, the lack of involvement of the known loci in two of the families indicates further genetic heterogeneity for BFIC.

Early predictors of outcome after mild traumatic brain injury (UPFRONT): an observational cohort study

BACKGROUND Mild traumatic brain injury (mTBI) accounts for most cases of TBI, and many patients show incomplete long-term functional recovery. We aimed to create a prognostic model for functional outcome by combining demographics, injury severity, and psychological factors to identify patients at risk for incomplete recovery at 6 months. In particular, we investigated additional indicators of emotional distress and coping style at 2 weeks above early predictors measured at the emergency department. METHODS The UPFRONT study was an observational cohort study done at the emergency departments of three level-1 trauma centres in the Netherlands, which included patients with mTBI, defined by a Glasgow Coma Scale score of 13-15 and either post-traumatic amnesia lasting less than 24 h or loss of consciousness for less than 30 min. Emergency department predictors were measured either on admission with mTBI-comprising injury severity (GCS score, post-traumatic amnesia, and CT abnormalities), demographics (age, gender, educational level, pre-injury mental health, and previous brain injury), and physical conditions (alcohol use on the day of injury, neck pain, headache, nausea, dizziness)-or at 2 weeks, when we obtained data on mood (Hospital Anxiety and Depression Scale), emotional distress (Impact of Event Scale), coping (Utrecht Coping List), and post-traumatic complaints. The functional outcome was recovery, assessed at 6 months after injury with the Glasgow Outcome Scale Extended (GOSE). We dichotomised recovery into complete (GOSE=8) and incomplete (GOSE≤7) recovery. We used logistic regression analyses to assess the predictive value of patient information collected at the time of admission to an emergency department (eg, demographics, injury severity) alone, and combined with predictors of outcome collected at 2 weeks after injury (eg, emotional distress and coping). FINDINGS Between Jan 25, 2013, and Jan 6, 2015, data from 910 patients with mTBI were collected 2 weeks after injury; the final date for 6-month follow-up was July 6, 2015. Of these patients, 764 (84%) had post-traumatic complaints and 414 (45%) showed emotional distress. At 6 months after injury, outcome data were available for 671 patients; complete recovery (GOSE=8) was observed in 373 (56%) patients and incomplete recovery (GOSE ≤7) in 298 (44%) patients. Logistic regression analyses identified several predictors for 6-month outcome, including education and age, with a clear surplus value of indicators of emotional distress and coping obtained at 2 weeks (area under the curve [AUC]=0·79, optimism 0·02; Nagelkerke R2=0·32, optimism 0·05) than only emergency department predictors at the time of admission (AUC=0·72, optimism 0·03; Nagelkerke R2=0·19, optimism 0·05). INTERPRETATION Psychological factors (ie, emotional distress and maladaptive coping experienced early after injury) in combination with pre-injury mental health problems, education, and age are important predictors for recovery at 6 months following mTBI. These findings provide targets for early interventions to improve outcome in a subgroup of patients at risk of incomplete recovery from mTBI, and warrant validation. FUNDING Dutch Brain Foundation.

Patients “At Risk” of Suffering from Persistent Complaints after Mild Traumatic Brain Injury: The Role of Coping, Mood Disorders, and Post-Traumatic Stress

Although most patients recover fully following mild traumatic brain injury (mTBI), a minority (15-25%) of all patients develop persistent post-traumatic complaints (PTC) that interfere with the resumption of previous activities. An early identification of patients who are at risk for PTC is currently performed by measuring the number of complaints in the acute phase. However, only part of this group will actually develop persisting complaints, stressing the need for studies on additional risk factors. This study aimed to compare this group of patients with many complaints with patients with few and no complaints to identify potential additional discriminating characteristics and to evaluate which of these factors have the most predictive value for being at risk. We evaluated coping style, presence of psychiatric history, injury characteristics, mood-related symptoms, and post-traumatic stress. We included 820 patients (Glasgow Coma Scale [GCS] score 13-15) admitted to three level-1 trauma centers as part of the UPFRONT-study. At 2 weeks after injury, 60% reported three or more complaints (PTC-high), 25% reported few complaints (PTC-low), and 15% reported no complaints (PTC-zero). Results showed that PTC-high consisted of more females (78% vs. 73% and 52%, p < 0.001), were more likely to have a psychiatric history (7% vs. 2% and 5%), and had a higher number of reported depression (22% vs. 6% and 3%, p < 0.001), anxiety (25% vs. 7% and 5%), and post-traumatic stress (37% vs. 27% and 19%, p < 0.001) than the PTC-low and PTC-zero groups. We conclude that in addition to reported complaints, psychological factors such as coping style, depression, anxiety, and post-traumatic stress symptoms had the highest predictive value and should be taken into account in the identification of at-risk patients for future treatment studies.

A Dutch family with benign hereditary chorea of early onset: differentiation from Huntington's disease

A large Dutch family of 88 members, running through five generations, is described with benign hereditary chorea of early onset. The clinical presentation was heterogeneous. The chorea manifested in late infancy or childhood, interfered with writing, was non-disabling, stable or even improved in adulthood in most cases, but was slowly progressive with gait impairment in some. There was mild dysarthria and normal intelligence. EEG brain CT-scanning and MRI were normal. Huntingtons disease was excluded by analysis of the I T 15 gene, which showed a normal number of the CAG trinucleotide repeats in two patients. It is concluded that benign hereditary chorea of early onset is an entity different from Huntingtons disease and that in cases of early onset chorea the diagnostic accuracy is markedly improved by DNA testing.

The juvenile head trauma syndrome: a trauma triggered migraine?

BACKGROUND The underlying mechanism of the juvenile head trauma syndrome (JHTS) is still uncertain, but it has been suggested that there is a role in cortical spreading depression, a phenomenon that is assumed to be a part of the pathophysiology of migraine. HYPOTHESIS We postulate that children affected by the JHTS are more susceptible to cortical spreading depression, caused by a genetic etiology similar to genetic factors in migraine. METHODS Children with the JHTS were selected and evaluated retrospectively in an observational case-control study in two Dutch trauma centers in the period between January 2008 and July 2012. RESULTS We included 33 patients with the JHTS, who were accounted for approximately 2.5% of the total number (1,342) of children seen at the emergency department with a mild head trauma. The prevalence of migraine in cases compared with controls did not differ. The proportion of patients with a first-degree relative with migraine was significantly higher in cases compared with controls (odds ratio, 2.69; 95% confidence interval, 1.16-6.22; p = 0.010). CONCLUSION The JHTS is a relatively rare phenomenon, seen in approximately 2.5% of all children seen at the emergency department with mild brain injury. This study demonstrates a significant relationship between the JHTS and a positive history of migraine in first-degree relatives.

Outpatient follow-up after mild traumatic brain injury: Results of the UPFRONT-study

ABSTRACT Objective: To investigate outpatient follow-up after mild traumatic brain injury (mTBI) by various medical specialists, for both hospitalized and non-hospitalized patients, and to study guideline adherence regarding hospital admission. Methods: Patients (n = 1151) with mTBI recruited from the emergency department received questionnaires 2 weeks (n = 879), 3 months (n = 780) and 6 months (n = 668) after injury comprising outpatient follow-up by various health care providers, and outcome defined by the Glasgow Outcome Scale Extended (GOS-E) after 6 months. Results: Hospitalized patients (60%) were older (46.6 ± 19.9 vs. 40.6 ± 18.5 years), more severely injured (GCS <15, 50% vs. 13%) with more Computed Tomography (CT) abnormalities on admission (21% vs. 2%) compared to non-hospitalized patients (p < 0.01) . Almost half of the patients visited a neurologist at the outpatient clinic within six months (60% of the hospitalized and 25% of the non-hospitalized patients (χ2 = 67.10, p < 0.01)), and approximately ten per cent consulted a psychiatrist/psychologist. Outcome was unfavourable (GOS-E <7) in 34% of hospitalized and 21% of non-hospitalized patients (χ2 = 11.89, p < 0.01). Conclusion: Two-thirds of all mTBI patients consult one or more specialists within six months after injury, with 30% having an unfavourable outcome. A quarter of non-hospitalized patients was seen at the outpatient neurology clinic, underling the importance of regular follow-up of mTBI patients irrespective of hospital admittance.