[The value of re-evaluation and thorough family history taking for the diagnostic work-up of chorea]. / Het diagnostisch proces bij chorea: het belang van heroverwegen en de familieanamnese.

The differential diagnosis of chorea encompasses a broad range of disorders. In psychiatry, tardive dyskinesia may be difficult to discern from other causes, particularly when the family history is negative. A 59-year-old man with an unclear medical history had been using risperidone for over a decade when we first saw him. He presented with severe dyskinesia in all extremities. The family history for neuropsychiatric disorders was negative. We interpreted the movement disorder as tardive dyskinesia, but later he turned out to suffer from Huntington’s disease. To improve diagnostic accuracy, we should have more frequently re-evaluated the differential diagnosis and our family history should have been more thorough. We outline the diagnostic considerations in patients presenting with chorea. Finally, we highlight the value of diagnostic re-evaluation and thorough family history taking to optimize diagnostic accuracy in neuropsychiatry.

Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort.

Spastic paraplegia type 7 is an autosomal recessive neurodegenerative disorder mainly characterized by progressive bilateral lower limb spasticity and referred to as a form of hereditary spastic paraplegia. Additional disease features may also be observed as part of a more complex phenotype. Many different mutations have already been identified, but no genotype-phenotype correlations have been found so far. From a total of almost 800 patients referred for testing, we identified 60 patients with mutations in the SPG7 gene. We identified 14 previously unreported mutations and detected a high recurrence rate of several earlier reported mutations. We were able to collect detailed clinical data for 49 patients, who were ranked based on a pure versus complex phenotype, ataxia versus no ataxia and missense versus null mutations. A generally complex phenotype occurred in 69% of all patients and was associated with a younger age at onset (trend with P = 0.07). Ataxia was observed in 57% of all patients. We found that null mutations were associated with the co-occurrence of cerebellar ataxia (trend with P = 0.06). The c.1409 G > A (p.Arg470Gln) mutation, which was found homozygously in two sibs, was associated with a specific complex phenotype that included predominant visual loss due to optical nerve atrophy. Neuropathology in one of these cases showed severe degeneration of the optic system, with less severe degeneration of the ascending tracts of the spinal cord and cerebellum. Other disease features encountered in this cohort included cervical dystonia, vertical gaze palsy, ptosis and severe intellectual disability. In this large Dutch cohort, we seem to have identified the first genotype-phenotype correlation in spastic paraplegia type 7 by observing an association between the cerebellar phenotype of spastic paraplegia type 7 and SPG7 null alleles. An overlapping phenotypic presentation with its biological counterpart AFG3L2, which when mutated causes spinocerebellar ataxia type 28, is apparent and possibly suggests that abnormal levels of the SPG7 protein impact the function of the mitochondrial ATPases associated with diverse cellular activities-protease complex (formed by SPG7 and AFG3L2) in the cerebellum. In addition, a missense mutation in exon 10 resulted in predominant optical nerve atrophy, which might suggest deleterious interactions of this SPG7 variant with its substrate OPA1, the mutated gene product in optic atrophy type 1. Functional studies are required to further investigate these interactions.

Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations.

BACKGROUND: In the clinically and genetically heterogeneous group of the hereditary spastic paraplegias (HSPs), mutations in the SPAST gene are most frequently found and cause a pure autosomal dominant form. OBJECTIVE: To provide the clinical and genetic characteristics of Dutch patients with HSP due to a SPAST mutation (SPG4). METHODS: SPAST mutation carriers were identified through a comprehensive national database search. Available medical records were reviewed. RESULTS: 151 mutation carriers carried 60 different changes in the SPAST gene, of which one was a known polymorphism, and 27 were novel. Missense mutations were most frequently found (39%). Clinical information was available from 72 mutation carriers. Age at onset ranged from 1 to 63 years with a bimodal peak distribution in the first decade and above age 30. The predominantly pure spastic paraplegia was accompanied by deep sensory disturbances and sphincter problems in almost 50%. An additional hand tremor was found in 10%. Patients with missense mutations and exon deletions did not reveal a distinctive phenotype. CONCLUSIONS: Dutch SPAST mutation carriers show a broad mutation spectrum, with 27 novel mutations in the present series. A bimodal peak distribution in age at onset was found and an accompanying tremor as peculiar feature of SPG4. The pathogenicity of S44L, the first exon 4 mutation, and a possible autosomal recessive mode of inheritance are discussed.

Postural instability in cerebellar ataxia: correlations of knee, arm and trunk movements to center of mass velocity.

The aim of this study was to investigate the correlations between body segment movements and center of mass (COM) velocity during pathological balance corrections of spinocerebellar ataxia (SCA) patients compared with controls, and to relate correlations indicating instability to EMG activity differences. Eighteen SCA patients and 21 age-matched controls were tested. Upright standing was perturbed using rotations of the support surface. We recorded body motion and surface EMG. For lateral perturbations peaks in COM lateral velocity were larger in SCA patients than controls. These peaks were correlated with increased ("hypermetric") trunk roll downhill and reduced uphill knee flexion velocity. Subsequent arm abduction partially corrected the lateral instability. Early balance correcting responses in knee and paraspinal muscles showed reduced amplitudes compared with normal responses. Later responses were consistent with compensation mechanisms for the lateral instability created by the stiffened knee and pelvis. We conclude that truncal hypermetria coupled with insufficient uphill knee flexion is the primary cause of lateral instability in SCA patients. Holding the knees and pelvis more rigid possibly permits a reduction in the controlled degrees of freedom and concentration on arm abduction to improve lateral instability. For backwards perturbations excessive posterior COM velocity coincided with marked trunk hypermetric flexion forwards. We concluded that this flexion and the ensuing backwards shift of the pelvis result from rigidity which jeopardizes posterior stability. Timing considerations and the lack of confirmatory changes in amplitudes of EMG activity suggest that lateral and posterior instability in SCA is primarily a biomechanical response to pelvis and knee rigidity resulting from increased muscle background activity rather than changed evoked responses.

CSF studies facilitate DNA diagnosis in familial Alzheimer's disease due to a presenilin-1 mutation.

In sporadic Alzheimer's disease (AD), cerebrospinal fluid (CSF) analysis is becoming increasingly relevant to establish an early diagnosis. We present a case of familial AD due to a presenilin-1 mutation in which CSF studies suggested appropriate DNA diagnostics. A 38 year old Dutch man presented with dementia, spastic paraparesis, and frontal executive function impairments, mimicking familial Creutzfeldt Jakob disease and frontotemporal dementia. CSF studies, revealing increased total tau and phosphorylated-tau levels with decreased amyloid-beta42, distinguished familial AD from Creutzfeldt Jakob disease and frontotemporal dementia. A causative p.L424R PSEN1 mutation was subsequently identified.

A clinical diagnostic algorithm for early onset cerebellar ataxia.

Early onset cerebellar Ataxia (EOAc) comprises a large group of rare heterogeneous disorders. Determination of the underlying etiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This may change the diagnostic work-up into a time-consuming, costly and not always rewarding task. In this overview, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS) presents a diagnostic algorithm for EOAc patients. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuro-imaging, laboratory investigations, genetic testing by array CGH and Next Generation Sequencing (NGS). In children with EOAc, this algorithm is intended to contribute to the diagnostic process and to allow uniform data entry in EOAc databases.

CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine.

Of the 18 missense mutations in the CACNA1A gene, which are associated with familial hemiplegic migraine type 1 (FHM1), only mutations S218L, R583Q and T666M were identified in more than two independent families. Including the four novel families presented here, of which two represent de novo cases, the R1347Q mutation has now been identified in six families. A genotype-phenotype comparison of R1347Q mutation carriers revealed a wide clinical spectrum ranging from (trauma triggered) hemiplegic migraine with and without ataxia, loss of consciousness and epilepsy. R1347Q is the third most frequent mutation in hemiplegic migraine patients and should therefore be screened with priority for confirmation of clinical diagnosis. This study clearly demonstrates that the availability of multiple families better reflects the full clinical spectrum associated with FHM1 mutations.

CSF hypocretin-1 levels are normal in multiple-system atrophy.

Sleep disturbances occur in 70% of the patients with multiple system atrophy (MSA). Disturbances of the hypothalamic hypocretin neurotransmission have been suggested as a possible cause. Since a systematic study of CSF hypocretin-1 levels in MSA has not yet been performed, we analysed CSF hypocretin-1 concentrations in 6 MSA-P and 6 MSA-C patients and 11 age-matched controls. We did not observe any differences from control values.

CSF neurofilament proteins in the differential diagnosis of dementia.

BACKGROUND: Neurofilament (NF) proteins are major cytoskeletal constituents of neurons. Increased CSF NF levels may reflect neuronal degeneration. OBJECTIVE: To investigate the diagnostic value of CSF NF analysis to discriminate in relatively young dementia patients between frontotemporal lobe degeneration (FTLD) and early onset Alzheimer's disease (EAD; onset < or = 65 years of age), and in elderly dementia patients between dementia with Lewy bodies (DLB) and late onset AD (LAD; onset > 65 years of age). METHODS: In CSF of 28 FTLD, 37 EAD, 18 DLB and 33 LAD patients, and 26 control subjects, we analysed NF light chain (NFL), phosphorylated NF heavy chain (pNFH), amyloid beta42 protein (Abeta42), total tau and tau phosphorylated at threonine 181 (p-tau181). RESULTS: CSF NFL levels were higher in FTLD patients compared with EAD patients (p<0.001), and diagnostic accuracy of p-tau181 and Abeta42 analysis improved with addition of NFL analysis (sensitivity 86%, specificity 100%). CSF pNFH levels were elevated in DLB, LAD and FTLD compared with controls (p<0.05) but no significant differences were found between the dementia groups. CONCLUSIONS: In the diagnostic workup of relatively young dementia patients, CSF NFL levels may play a role in the discrimination between FTLD and EAD, especially in combination with Abeta42 and p-tau181 analysis.

Cerebellar ataxia and congenital disorder of glycosylation Ia (CDG-Ia) with normal routine CDG screening.

Cerebellar ataxia can have many genetic causes among which are the congenital disorders of glycosylation type I (CDG-I). In this group of disorders, a multisystem phenotype is generally observed including the involvement of many organs, the endocrine, hematologic and central nervous systems. A few cases of CDG-Ia have been reported with a milder presentation, namely cerebellar hypoplasia as an isolated abnormality. To identify patients with a glycosylation disorder, isofocusing of plasma transferrin is routinely performed. Here, we describe two CDG-Ia patients,who presented with mainly ataxia and cerebellar hypoplasia and with a normal or only slightly abnormal transferrin isofocusing result. Surprisingly, the activity of the corresponding enzyme phosphomannomutase was clearly deficient in both leucocytes and fibroblasts. Therefore, in patients presenting with apparently recessive inherited ataxia caused by cerebellar hypoplasia and an unknown genetic aetiology after proper diagnostic work-up, we recommend the measurement of phosphomannomutase activity when transferrin isofocusing is normal or inconclusive.

What's wrong with Tourette syndrome?

Gilles de la Tourette Syndrome (Tourette Syndrome, TS) and related tic disorders have known fascinated researchers since their initial description around 1884 by the French marquis Georges Albert Edouard Brutus Gilles de la Tourette. Particularly the "cause" of the disorder has been a much sought-after prize, but unfortunately this goal has appeared remarkably elusive. Many clues have been pursued, both genetic and environmental factors, but no compelling major contribution to the pathogenesis of the disease has yet emerged. What's wrong with TS? Is it lack of data or lack of concepts? It should be noted that TS is not unique in this respect. Despite decades of intensive data gathering, many prevalent psychiatric disorders, such as schizophrenia, major depressive disorder or obsessive-compulsive disorder still face a more or less similar situation.

CSF biomarker profiles do not differentiate between the cerebellar and parkinsonian phenotypes of multiple system atrophy.

BACKGROUND: Multiple system atrophy (MSA) can clinically be divided into the cerebellar (MSA-C) and the parkinsonian (MSA-P) variants. It is unknown whether the variation in clinical expression is also reflected by a different underlying neurochemical profile. METHODS: We analyzed brain specific proteins and neurotransmitter metabolites in cerebrospinal fluid (CSF) of 26 patients with MSA-C and 19 with MSA-P. RESULTS: No differences were found between MSA-C and MSA-P. CONCLUSION: Our results suggest that the clinical and in part pathological distinction between the two clinical MSA phenotypes is not reflected by the neurochemical composition of CSF.

[Embrace, integrated primary care for older adults]. / SamenOud, geïntegreerde ouderenzorg in de eerste lijn.

OBJECTIVE: To examine the impact of Embrace (Dutch: SamenOud), a new primary care model for community-living people aged over 75 years on perceived quality of care. DESIGN: Randomized controlled trial in 15 general practices in the East Groningen region of the Netherlands. METHOD: In the period January 2012-March 2013, 1456 general practice patients aged 75 years and older were stratified on the basis of self-reporting into 3 risk profiles: 'robust', 'frail' and 'complex care needs', and then randomized to the intervention or the control arm. Intervention consisted of care and support from an elderly-care team consisting of a specialist in Gerontology, a district nurse, and a social worker. Intensity and duration of the care and support were dependent on risk profile. The primary outcome measure was quality of care as reported by participants; the secondary outcome measure was the extent of implementation as reported by the caregivers. RESULTS: The level of perceived quality of care after 12 months was slightly higher in the intervention arm than in the control arm, but the effect size was quite small. The difference was significant in elderly people with the risk profiles 'frail' and 'complex care needs'; robust elderly people did not experience a significant difference. The caregivers reported increased implementation of integrated care (effect size 0.71, that means average). CONCLUSION: Embrace slightly improved the perceived quality of care, particularly for elderly people with complex care needs for whom case management was organised. Caregivers judged implementation of integrated care to be greatly improved, though there was still room for further improvement. Further research should be carried out into the effectiveness of integrated primary care for the elderly on health, service-use and healthcare costs.

Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis.

BACKGROUND: International prevalence estimates of autosomal dominant cerebellar ataxias (ADCA) vary from 0.3 to 2.0 per 100,000. The prevalence of ADCA in the Netherlands is unknown. Fifteen genetic loci have been identified (SCA-1-8, SCA-10-14, SCA-16, and SCA-17) and nine of the corresponding genes have been cloned. In SCA-1, SCA2, SCA3, SCA6, SCA7, SCA-12 and SCA-17 the mutation has been shown to be an expanded CAG repeat. Previously, the length of the CAG repeat was found to account for 50 to 80% of variance in age at onset. Because of heterogeneity in encoded proteins, different pathophysiologic mechanisms leading to neurodegeneration could be involved. The relationship between CAG repeat length and age at onset would then differ accordingly. METHOD: Based on the results of SCA mutation analysis in the three DNA diagnostic laboratories that serve the entire Dutch population, the authors surveyed the number of families and affected individuals per SCA gene, as well as individual repeat length and age at onset. Regression analysis was applied to study the relationship between CAG repeat length and age at onset per SCA gene. The slopes of the different regression curves were compared. RESULTS: On November 1, 2000, mutations were found in 145 ADCA families and 391 affected individuals were identified. The authors extrapolated a minimal prevalence of 3.0 per 100,000 (range 2.8 to 3.8/100,000). SCA3 was the most frequent mutation. CAG repeat length contributed to 52 to 76% of age at onset variance. Regression curve slopes for SCA-1, SCA2, SCA3, and SCA7 did not differ significantly. CONCLUSIONS: The estimated minimal prevalence of ADCA in the Netherlands is 3.0 per 100,000 inhabitants. Except for SCA6, the relationship between age at onset and CAG repeat expansion does not differ significantly between SCA-1, SCA2, SCA3, and SCA7 patient groups in our population, indicating that these SCA subtypes share similar mechanisms of polyglutamine-induced neurotoxicity, despite heterogeneity in gene products.

Drug-induced hyperthermia in Huntington's disease.

Until now, only three patients with Huntington's disease (HD) and a neuroleptic malignant syndrome (NMS) have been reported in the literature. We describe four cases with advanced stage Huntington's disease who within a period of one year developed drug-induced hyperthermia, either the neuroleptic malignant syndrome, or the serotonin syndrome. Possible contributing factors that may have been specific for HD patients could be identified and included advanced neurological disease with severe illness, occurrence in summer, with possible infectious disease, dehydration, and pre-existing extra-pyramidal signs that may mask incipient NMS/serotonin syndrome. Measures to avoid these potentially lifethreatening conditions are discussed.

Cutaneous reflexes from the foot during gait in hereditary spastic paraparesis.

OBJECTIVE: It is known that P2 cutaneous reflexes from the foot show phase-dependent modulation during gait. The role of the motor cortex and the cortico-spinal tract in these reflexes and their modulation is unknown. Patients with hereditary spastic paraparesis (HSP) have a lesion in the cortico-spinal tract and may show deficits in P2 reflexes and/or their modulation. METHODS: Reflex responses of tibialis anterior and biceps femoris after sural nerve stimulation in 10 HSP-patients were compared with those in 10 healthy subjects. The reflexes were studied at two different moments in the step cycle during walking on a treadmill. RESULTS: Both patients and controls showed a phase-dependent modulation of P2 responses. For the individual muscles, no significant difference in reflex activity was observed between HSP-patients and the controls. However, when all muscles were taken together, the reflex activity for the controls was significantly higher than for the patients. CONCLUSIONS: The results of this study suggest that the cortico-spinal tract is involved in the regulation of the amplitude of the P2 responses and their phase-dependent modulation.

Brain-specific proteins in cerebrospinal fluid for the diagnosis of neurodegenerative diseases.

Neurodegenerative disorders have traditionally been classified according to clinical criteria, e.g. as dementia syndromes (the best known is Alzheimer's disease) or as movement disorders (e.g. Parkinson's disease). Another subdivision is based on recent insights into the respective pathogenetic mechanisms, leading to the recognition of so-called tauopathies and alpha-synucleinopathies. It is this increased knowledge of the underlying (neuro)pathological mechanisms that has sparked interest in studies aimed at the identification of disease-specific biomarkers in cerebrospinal fluid (CSF) for this field of neurological disorders. This review deals with the recent progress that has been made in identification, quantification and subsequent validation of brain-specific proteins in CSF for the diagnosis of various neurodegenerative disorders. Development of disease-specific CSF biomarkers will undoubtedly add to the process of differential diagnosis early in the course of the disease.

Longitudinal analysis of hearing loss in a case of hemosiderosis of the central nervous system.

OBJECTIVE: To describe cochleovestibular aspects of superficial hemosiderosis of the central nervous system. BACKGROUND: Superficial hemosiderosis of the central nervous system is a rare disease in which cochleovestibular impairment, cerebellar ataxia, and myelopathy are the most frequent signs. Chronic recurrent subarachnoidal hemorrhage with bleeding into the cerebrospinal fluid is the cause of deposition of hemosiderin in leptomeningeal and subpial tissue, cranial nerves, and spinal cord. Removing the cause of bleeding can prevent irreversible damage to these structures. Because this is the only effective treatment, an early diagnosis is crucial. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENT: A 72-year-old woman with superficial hemosiderosis of the central nervous system that developed when she was age 39. METHODS: Neurologic and imaging diagnostic examinations and longitudinal evaluation of cochleovestibular features were performed. Neurosurgery was not performed. RESULTS: Progressive bilateral sensorineural hearing loss and severe vestibular hyporeflexia developed within 15 years, which can be attributed to lesions in the cochleovestibular system. Additional pathology of the central nervous system developed later. CONCLUSION: The patient demonstrated cochlear and vestibular findings that are typical of this pathologic condition. It is the first documented case with extensive serial audiometry used to precisely outline the degree of hearing deterioration during the course of the disease.

[Friedrich's ataxia: clinical difficulties and genetic possibilities]. / De ataxie van friedreich: klinische moeilijkheden en genetische mogelijkheden.

Atypical Friedreich's ataxia was diagnosed by DNA-analysis in 4 patients, 2 men aged 70 and 67 and 2 women aged 32 and 37, who had features that included an onset of ataxia after the age of 25, retained tendon reflexes or hyperreflexia, absence of Babinski's sign, and/or a slowly progressive course. Friedreich's ataxia is the most frequent autosomal recessive cerebellar ataxia. Classical characteristics of the disease are a progressive cerebellar ataxia with an onset before the age of 25, loss of lower extremity tendon reflexes, and bilateral Babinski's sign. However, DNA-diagnostic testing based upon the detection of expanded GAA-repeats in the X25-gene, has shown that the clinical spectrum is broader than was previously assumed.

[The possible suppression of Alzheimer's disease by nonsteroidal anti-inflammatory drugs]. / Het mogelijk remmende effect van niet-steroïde anti-inflammatoire geneesmiddelen op de ziekte van Alzheimer.

Ever since inflammatory mediators were detected in and around amyloid plaques in the brain of patients with Alzheimer's disease, there has been great interest in the inflammatory hypothesis and the possibility of treating Alzheimer's disease with anti-inflammatory drugs. Various epidemiological studies have now demonstrated that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is indeed associated with a reduced risk of developing Alzheimer's disease. The effect of NSAIDs in Alzheimer's disease is probably mediated by activation of the peroxisome proliferator-activated receptor-gamma. Administration of NSAIDs in a mouse model of Alzheimer's disease appears to suppress amyloid plaque formation and inflammatory mediators. These findings suggest that NSAIDs may also be able to slow down Alzheimer's disease progression. So far, only one small clinical trial has shown that treatment with NSAIDs significantly delayed cognitive decline in Alzheimer's disease patients. Large randomized double-blind placebo-controlled trials are needed to provide definitive evidence that NSAIDs have a therapeutic effect on Alzheimer's disease.