Aceruloplasminemia presents as Type 1 diabetes in non-obese adults: a detailed case series.

AIM: To detect features that might lead to the early diagnosis and treatment of aceruloplasminemia, as initiation of treatment before the onset of neurological symptoms is likely to prevent neurological deterioration. METHODS: The PubMed and OMIM databases were searched for published cases of aceruloplasminemia. Diagnostic criteria for aceruloplasminemia were undetectable or very low serum ceruloplasmin, hyperferritinemia and low transferrin saturation. Clinical, biochemical and radiological data on the presentation and follow-up of the cases were extracted and completed through e-mail contact with all authors. RESULTS: We present an overview of 55 aceruloplasminemia cases, including three previously unreported cases. Diabetes mellitus was the first symptom related to aceruloplasminemia in 68.5% of the patients, manifesting at a median age of 38.5 years, and often accompanied by microcytic or normocytic anaemia. The combination preceded neurological symptoms in almost 90% of the neurologically symptomatic patients and was found 12.5 years before the onset of neurological symptoms. CONCLUSIONS: There is a diagnostic window during which diabetes and anaemia are present although there is an absence of neurological symptoms. Screening for aceruloplasminemia in adult non-obese individuals presenting with antibody-negative, insulin-dependent diabetes mellitus and unexplained anaemia is recommended. The combination of ferritin and transferrin saturation provides a sensitive initial measure for aceruloplasminemia.

Recent advances in progressive supranuclear palsy: a review.

Progressive Supranuclear Palsy has been used over decades as a term denoting an uniform disorder with progressive parkinsonism with early falls, vertical supranulcear gaze palsy, pseudobulbar dysfunction and cognitive decline. Over the last decade, heterogeneity of the disease into different clinical subtypes has been recognized in clinicopathological studies. Although neuroimaging features and laboratory findings may support the diagnosis, true biomarkers are still lacking in the clinical setting. Neuronal and glial tau positive aggregates are predominantly found in basal ganglia and brainstem, and the significant association of PSP with the common H1 tau haplotype likely points to a pathophysiological role of the tau protein in the disease process. Future genetic studies of familial cases and an ongoing genome-wide association study of large series of pathological-proven cases may reveal additional genetic factors in the near future.

Familial aggregation of parkinsonism in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age- and sex-matched control group. METHODS: Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age- and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases. RESULTS: Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99-7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas. CONCLUSION: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy.

Frontal presentation in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive hypokinetic rigid disorder with supranuclear gaze palsy and frequent falls. Although clinical consensus criteria are available, an atypical presentation may lead to clinical misdiagnosis in the initial phase. In the present study we investigated the clinical presentation of PSP and its relationship to initial clinical diagnosis and survival. METHODS: We ascertained patients with PSP in a prospective cohort by nationwide referral from neurologists and nursing home physicians. All patients underwent a structural interview and clinical examination before entering the study. Medical records were reviewed for the presence of symptoms during the first 2 years. RESULTS: A total of 152 patients ascertained between 2002 and 2005 fulfilled the international consensus criteria for PSP. Categorical principal component analysis of clinical symptoms within the first 2 years showed apart from a cluster of typical PSP symptoms, the clustering of cognitive dysfunction and behavioral changes. Further analysis showed that 20% of patients had a predominant frontal presentation with less than two other PSP symptoms. Survival analysis showed that this subgroup had a similar prognosis to that of the total group of patients with PSP. CONCLUSIONS: There exists a subgroup of patients with progressive supranuclear palsy (PSP) with a predominant frontal presentation, who progressed into typical PSP over the course of the disease.

[Progressive supranuclear palsy; an unusual form of parkinsonism]. / Progressieve supranucleaire verlamming; een bijzondere vorm van parkinsonisme.

Progressive supranuclear palsy is a neurodegenerative disorder accompanied by parkinsonism, disturbances of eye movements, pseudobulbar palsy and often cognitive decline. Onset of disease is usually between 50-70 years of age and mean survival is 5-8 years. The prevalence of PSP has been estimated at around 5 per 100,000, although exact figures for the population of the Netherlands are not yet available. International consensus criteria differentiate between possible, probable and definite PSP; the latter requiring neuropathological confirmation. An extensive differential diagnosis may be made early in the course of the disease, but at a later stage development of the characteristic symptoms will make diagnosis easier. Imaging techniques can lend support to the clinical diagnosis to a limited extent, although they lack sufficient specificity to confirm it. PSP is a 'tauopathy' characterized by aggregates of abnormal tau protein in the basal ganglia and brainstem. Some mutations in the tau gene can cause a clinical and pathological picture similar to that of PSP, although most patients with sporadic and familial PSP do not have tau mutations. Various studies have found a strong association between PSP and a specific tau haplotype (H1 haplotype), but its role in the pathophysiological mechanism of PSP is still unclear and needs further research.

How to select patients with normal pressure hydrocephalus for shunting.

The objective was to compare predictive values of clinical and CT findings, co-existing cerebrovascular disease (CVD) and CSF outflow resistance (Rcsf) for outcome of shunting in NPH. A group of 95 NPH patients was shunted and followed for one year. Gait disturbance and dementia were quantified by an NPH scale (NPHS) and handicap by the modified Rankin scale (MRS). Improvement was defined as a change of at least 15% in NPHS and one grade in MRS at last follow-up. Clinical and CT findings at entry were classified as typical or not typical for NPH. CVD was defined as a history of stroke or CT-scans showing infarcts or moderate to severe white matter hypodense lesions. Clinical and CT findings typical for NPH, absence of CVD and Rcsf > 18 mmHg/ml/min were positive tests and the reciprocal outcomes negative tests. Typical clinical and CT findings were found in 69% and 68%, CVD (history of stroke n = 14, infarcts on CT n = 13, leucoaraiosis n = 32) in 47% and Rcsf > 18 in 38% of patients. The ratio of patients classified as improved in both scales was significantly greater for those with positive than negative tests. Mean improvement differed the most between patients with and without CVD. Using logistic regression analysis Rcsf > 18 was the only significant predictor of improvement in NPHS (OR 4.4, 95% CI 1.3-16.7) and typical CT findings in MRS (OR 5.6, 95% CI 1.8-17.9). We conclude that CVD is an important predictor of poor outcome. The best strategy is to shunt NPH patients if Rcsf is > 18 mmHg/ml/min or, when Rcsf is lower, if CT findings are typical for NPH and there is no or limited CVD.

Cerebral hemodynamics before and after shunting in normal pressure hydrocephalus.

OBJECTIVE: To study the relationship between cerebral hemodynamics and clinical performance in normal pressure hydrocephalus (NPH), before and after surgery. MATERIAL AND METHODS: Ten patients were studied prospectively before and 3 months after shunt surgery by means of transcranial Doppler (TCD). Clinical performance was scored by means of an NPH scale and the modified Rankin scale. RESULTS: Peak systolic and mean cerebral blood flow velocity (MCV) were lower and cerebrovascular CO2 reactivity was higher after shunt surgery. The three patients with clinical improvement had higher preoperative end diastolic cerebral blood flow velocity and MCV. All postoperative cerebral blood flow velocities were higher in patients with clinical improvement. CONCLUSION: Our data suggest that higher cerebral blood flow velocity before surgery in patients with NPH is related to clinical improvement after shunt surgery. Cerebral hemodynamic parameters may develop into predictors of successful shunt surgery in patients with normal pressure hydrocephalus.

Snowboarder's talus fracture. Mechanism of injury.

Fracture of the lateral process of the talus is an injury unique to snowboarders and is of particular clinical relevance because it masquerades as an anterolateral ankle sprain and is difficult to detect on standard radiographic views. Misdiagnosis can lead to long-term morbidity in a young and active population, with ensuing severe degeneration of the subtalar joint. To date, the precise mechanism of injury has not been established, making it difficult to identify potential preventive strategies in equipment design or snowboarding technique. Fracture of the lateral process of the talus in snowboarders has been thought to result from pure dorsiflexion and inversion combined with axial loading. We hypothesized, however, that external rotation is a key component of the mechanism of injury. Ten cadaveric ankles were mounted on a materials testing machine in a position of fixed dorsiflexion and inversion. All ankles were loaded to failure axially, with or without combined external rotation. No fractures occurred after axial loading in dorsiflexion and inversion, but six of eight specimens sustained fractures of the lateral process of the talus when similarly loaded with external rotation added, supporting our hypothesis. Further study is needed to evaluate the relationship between various types of snowboarding equipment and fracture mechanism.

[Suspected amyotrophic lateral sclerosis? Don't forget diagnostic imaging of the spine]. / Vermoeden van amyotrofische laterale sclerose? Vergeet afbeeldend onderzoek van de wervelkolom niet.

Two patients, men aged 35 and 72 years, had progressive muscle weakness, lower motor neuron signs in all extremities and upper motor neuron signs in the legs. There were no major sensory signs on examination. The clinical picture very much resembled amyotrophic lateral sclerosis (ALS), although there were never brain stem signs. Myelopathy and polyradiculopathies caused by a tandem cervical and lumbar spinal stenosis explained the clinical picture. Cervical MRI and lumbar CT confirmed this diagnosis. Laminectomy was done, after which both patients remained with unchanged symptoms. Tandem spinal stenosis should be part of the differential diagnosis of ALS. Imaging of the spine is necessary to confirm this diagnosis, and in the absence of bulbar signs always necessary prior to the diagnosis of ALS.

Inclusion body myositis masquerading as polymyositis: a case study.

A case of inclusion body myositis masquerading as unresponsive polymyositis is presented. A 56-year-old woman diagnosed with "biopsy-proven" polymyositis in 1991 was referred to our clinic in 1997 with progressive, painless weakness that was unresponsive to steroid therapy. Further evaluation, including electromyography and review of the original muscle biopsy specimen, found a diagnosis of inclusion body myositis, leading to a change in the patient's prognosis and management. Inclusion body myositis is frequently mistaken for polymyositis, despite the fact that it is now the most common inflammatory myopathy affecting people older than 50 years. The purpose of this report is to increase awareness of this disease, to enhance early diagnosis, and to ensure appropriate management. We discuss the clinical findings, pathogenesis, and physiatric management, as well as compare this disease with other idiopathic inflammatory myopathies.

Manual scapular stabilization: its effect on shoulder rotational range of motion.

OBJECTIVES: To study the effect of a recently described method of measuring shoulder rotational range of motion in which the scapula is manually stabilized, and to determine the reliability of that technique compared with measurements taken with the scapula unstabilized. DESIGN: Fifty high school athletes underwent measurement of shoulder rotational range of motion with and without the scapula manually stabilized. Measurements were performed by two groups of physical therapists blinded to the movement results, with repeat measurements performed 5 days later. RESULTS: Rotational motion measured with the scapula stabilized was significantly less than when it was measured with the scapula unstabilized. Reliability was comparable for the two techniques when measuring external rotation, but the new technique was more reliable for measuring internal rotation. CONCLUSION: Scapular stabilization should be used when measuring internal rotation of the shoulder to obtain more accurate measurement of pure glenohumeral rotation. The technique described is promising, but warrants further refinement before it can be recommended for widespread clinical use. With practice, in experienced clinicians' hands, this technique may be the most reliable method for measuring outcome in clinical trials and for following clinically significant rotational motion deficits.

The Dutch normal-pressure hydrocephalus study. How to select patients for shunting? An analysis of four diagnostic criteria.

BACKGROUND: Comparison of the predictive value of four "diagnostic tests" for the outcome of shunting in patients with normal-pressure hydrocephalus (NPH). METHODS: Ninety-five NPH patients who received shunts were followed for 1 year. Gait disturbance and dementia were quantified by an NPH scale and handicap by a modified Rankin scale. Primary outcome measures were differences between the preoperative and last scores on both the NPH scale and the modified Rankin scale. Clinical and computed tomographic (CT) findings typical of NPH, absence of cerebrovascular disease, and a resistance to outflow of cerebrospinal fluid (CSF) >/= 18 mmHg/ml/minute were designated as a positive test outcome; clinical and CT findings compatible with NPH, presence of cerebrovascular disease, and an outflow resistance < 18 mmHg/ml/minute as a negative test outcome. RESULTS: For each of the four tests the percentage of patients classified as improved was significantly greater for those with positive than with negative test results. Measurement of CSF outflow resistance was the only significant prognostic factor for the improvement ratio in NPH scale and CT in the modified Rankin scale according to multivariate logistic regression analysis. The accurate predictive value of the combination of typical clinical and CT findings was 0.65, that of the positive test results of outflow resistance, clinical and CT findings was 0.74. CONCLUSION: The best strategy is to shunt NPH patients if their outflow resistance is >/= 18 mmHg/ml/minute or, when the outflow resistance is lower, if their clinical as well as their CT findings are typical of NPH.

Dutch Normal-Pressure Hydrocephalus Study: the role of cerebrovascular disease.

OBJECT: This study was conducted to determine the prevalence of cerebrovascular disease and its risk factors among patients with normal-pressure hydrocephalus (NPH) and to assess the influence of these factors on the outcome of shunt placement. METHODS: A cohort of 101 patients with NPH underwent shunt placement and was followed for 1 year. Gait disturbance and dementia were quantified using an NPH scale and handicap was determined using a modified Rankin scale (mRS). Primary outcome measures consisted of the differences between preoperative and last NPH scale and mRS scores. The presence of risk factors such as hypertension, diabetes mellitus, cardiac disease, peripheral vascular disease, male gender, and advancing age was recorded. Cerebrovascular disease was defined as a history of stroke or a computerized tomography (CT) scan revealing infarcts or moderate-to-severe white matter hypodense lesions. The prevalence of risk factors for cerebrovascular disease was higher in the 45 patients with cerebrovascular disease than the 56 without it. Risk factors did not influence outcome after shunt placement. Intent-to-treat analysis revealed that the mean improvement in the various scales was significantly less for patients with a history of stroke (14 patients), CT scans revealing infarctions (13), or white matter hypodense lesions (32 patients) than for those without cerebrovascular disease. The proportion of patients who responded to shunt placement was also significantly lower among patients with than those without cerebrovascular disease (p=0.02). CONCLUSIONS: The authors identified a subgroup of patients with NPH and cerebrovascular disease who showed disappointing results after shunt placement. Cerebrovascular disease was an important predictor of poor outcome.

Snowboarding injuries: general patterns, with a focus on talus fractures.

Injury patterns in snowboarding differ from those in Alpine skiing. Snowboarders tend to have fewer knee and thumb injuries than skiers but more upper-extremity trauma, fractures in general, and ankle injuries. Of particular concern in snowboarding is fracture of the lateral process of the talus (LPT), which masquerades as an inversion ankle sprain, is often missed, and can lead to significant disability. Signs are typically similar to those of inversion sprains, but pain on palpation of the lateral process can be helpful in diagnosis. Standard radiographs often do not show the fracture, so CT or lateral tomography may be required. The most minor, nondisplaced LPT injuries may heal with casting and rehab, but more severe fractures typically require surgery.

Does CSF outflow resistance predict the response to shunting in patients with normal pressure hydrocephalus?

The value of the measurements of CSF outflow resistance (Rcsf) relative to predicting outcome after shunting was studied. In a group of 101 patients with mainly idiopathic normal pressure hydrocephalus (NPH) Rcsf was obtained by lumbar constant flow infusion. Gait disturbance and dementia were quantified using an NPH scale (NPHS) and disability by the Modified Rankin scale (MRS). Patients were assessed before and at 1, 3, 6, 9 and 12 months after surgery. Outcome measures were differences between the preoperative and last NPHS and MRS scores. Improvement was defined as a change of > or = 15% in NPHS and > or = 1 grade in MRS. Intention-to-treat analysis of all patients at one year yielded improvement of 57% in NPHS and 59% in MRS. Efficacy analysis, excluding comorbidity unrelated to NPH, revealed positive predictive values of around 80% at Rcsf < 18, and between 90% and 100% at Rcsf > or = 18 mm Hg/ml/min. For Rcsf > or = 18, the likelihood ratios were also higher. We conclude that the best predictor of the response to shunting is an Rcsf > or = 18 mm Hg/ml/min. Since two-thirds of the patients with Rcsf < 18 showed improvement as well, these patients should not be denied shunting.

Dutch Normal-Pressure Hydrocephalus Study: randomized comparison of low- and medium-pressure shunts.

OBJECT: The goal of this prospective study was to compare outcome after placement of a low- or medium-pressure shunt in patients with normal-pressure hydrocephalus (NPH). METHODS: Ninety-six patients with NPH were randomized to receive a low-pressure ventriculoperitoneal shunt (LPV; 40 +/- 10 mm H2O) or medium high-pressure ventriculoperitoneal shunt (MPV; 100 +/- 10 mm H2O). The patients' gait disturbance and dementia were quantified by applying an NPH scale, and their level of disability was evaluated by using the modified Rankin scale (mRS). Patients were examined prior to and 1, 3, 6, 9, and 12 months after surgery. Primary outcome measures were determined by differences between preoperative and last NPH scale scores and mRS grades. The LPV and MPV shunt groups were compared by calculating both the differences between mean improvements and the proportions of patients showing improvement. Intention-to-treat analysis of mRS grades yielded a mean improvement of 1.27 +/- 1.41 for patients with LPV shunts and 0.68 +/- 1.58 for patients with MPV shunts (p = 0.06). Improvement was found in 74% of patients with LPV shunts and in 53% of patients with MPV shunts (p = 0.06) and a marked-to-excellent improvement in 45% of patients with LPV shunts and 28% of patients with MPV shunts (p = 0.12). All outcome measures indicated trends in favor of the LPV shunt group, with only the dementia scale reaching significance. After exclusion of serious events and deaths unrelated to NPH, efficacy analysis showed the advantage of LPV shunts to be diminished. Reduction in ventricular size was also significantly greater for patients in the LPV shunt group (p = 0.009). Subdural effusions occurred in 71% of patients with an LPV shunt and in 34% with an MPV shunt; however, their influence on patient outcome was limited. CONCLUSIONS: Outcome was better for patients who had an LPV shunt than for those with an MPV shunt, although most differences were not statistically significant. The authors advise that patients with NPH be treated with an LPV shunt.

Dutch normal-pressure hydrocephalus study: prediction of outcome after shunting by resistance to outflow of cerebrospinal fluid.

The authors examined whether measurement of resistance to outflow of cerebrospinal fluid (Rcsf) predicts outcome after shunting for patients with normal-pressure hydrocephalus (NPH). In four centers 101 patients (most of whom had idiopathic NPH) who fulfilled strict entry criteria underwent shunt placement irrespective of their level of Rcsf obtained by lumbar constant flow infusion. Gait disturbance and dementia were quantified by using an NPH scale and the patient's level of disability was assessed by using the modified Rankin scale (mRS). In addition the Modified Mini-Mental State Examination was performed. Patients were assessed prior to and 1, 3, 6, 9, and 12 months after surgery. Primary outcome measures were based on differences between the preoperative and last NPH scale scores and mRS grades. Improvement was defined as a change measuring at least 15% in the NPH scale score and at least one mRS grade. Intention-to-treat analysis of all patients at 1 year yielded improvement for 57% in NPH scale score and 59% in mRS grade. Efficacy analysis, excluding serious events and deaths that were unrelated to NPH, was performed for 95 patients. Improvement rose to 76% in NPH scale score and 69% in mRS grade. Six cut-off levels of Rcsf were related to improvement in NPH scale score using two-by-two tables. Positive predictive values were approximately 80% for an Rcsf of 10, 12, or 15 mm Hg/ml/minute, 92% for an Rcsf of 18 mm Hg/ml/minute, and 100% for an Rcsf of 24 mm Hg/ml/minute. Negative predictive values were low. More important was the highest likelihood ratio of 3.5 for an Rcsf of 18 mm Hg/ml/minute. Extensive comorbidity was a major prognostic factor. Measurement of Rcsf reliably predicts outcome if the limit for shunting is raised to 18 mm Hg/ml/minute. At lower Rcsf values the decision depends mainly on the extent to which clinical and computerized tomography findings are typical of NPH.

Dutch normal pressure hydrocephalus study: baseline characteristics with emphasis on clinical findings.

We present the baseline characteristics of 101 patients with normal pressure hydrocephalus (NPH), entering a study that evaluates the diagnostic reliability of CSF outflow resistance. Patients were assessed by a gait scale consisting of 10 features of walking and the number of steps and seconds necessary for 10 m, a dementia scale comprising the 10 word test, trail making, digit span and finger tapping, the modified Mini Mental State Examination (3MSE) and the modified Rankin scale (MRS). Inclusion criteria were a gait and dementia scale ≥ 12 (range 2-40), a MRS ≥ 2 and a communicating hydrocephalus on CT. Gait disorder and dementia varied from mild to severe leading to MRS 2 in 17%, MRS 3 in 34%, MRS 4 in 21%, MRS 5 in 16% and MRS 6, including akinetic mutism, in 12%. Only one patient showed both normal tandem walking and turning. Small steps, reduced foot floor clearance and wide base were also frequently seen in the 67 patients walking independently; 34 needed assistance or could not walk at all. Applying the 3MSE, 64% were demented; the remaining 36% exhibited a milder cognitive deficit. The 10 word test and trail making decreased with increasing dementia. Digit span and finger tapping declined in the most demented patients. This group of elderly patients with NPH, mostly of the idiopathic type, proved to be vulnerable because of considerable disability and comorbidity.

Early diet in preterm babies and developmental status at 18 months.

424 preterm infants were randomly assigned a standard "term" formula or a nutrient-enriched "preterm" formula as sole diets (trial A) or as supplements to mother's own expressed milk (trial B) for a median of 4 weeks postnatally. 18 months post term, blind evaluation of 377 survivors showed that those previously fed preterm rather than term formula had major developmental advantages, more so in motor than mental function; the advantages, in both mental and motor scores, were especially striking in small-for-gestational-age infants and in males. For motor development index in trial A, this advantage was 15 points; in infants born small for gestation, it was 23 points (nearly 1.5 SD). Moderate developmental impairment (developmental index less than 85), notably motor impairment, was considerably more common in the group fed term formula. Infants fed preterm formula also had a small benefit in social maturity quotient. Thus, a short period of early dietary manipulation in preterm infants had major consequences for later development, which suggests that the first weeks may be critical for nutrition.