Are the skills of neurological assessment in need of resuscitation?

The aim of this paper is to outline the background to several recent papers which highlight deficiencies in acute neurological care­all of which highlight (to differing degrees) issues in relation to neurological assessment with some proposed solutions. Given that 10% of acute emergency admissions are for neurological conditions (up to 20% if stroke included), this should be of concern to all acute medical physicians.

The inpatient neurology consultation service: value and cost.

Neurological conditions comprise a significant proportion of patient admissions to hospital but, in the majority of cases, are admitted under the care of non-neurological physicians. As a consequence, neurological ward consultations are commonly requested by the admitting medical teams to review diagnoses and management plans. The outcomes of neurological ward consultations were examined and the time required for the referral process recorded by performing a detailed prospective three-month audit of inpatient referrals to the neurology service. The consultations of 120 patients were recorded, categorised and analysed. These consultations were beneficial in the vast majority of cases, with a clear impact on patient diagnoses or management plans. The consultation process was time consuming, however, both in respect of the initial review, but also with follow-up visits. This audit highlights the importance of neurological input in the diagnosis and management of hospital inpatients. The time taken for this process should be resourced appropriately.

Novel GCH1 variant in Dopa-responsive dystonia and Parkinson's disease.

BACKGROUND: GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family. METHODS: We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed. RESULTS: We have identified a novel missense variant, c.5A > G, p.(Glu2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype. CONCLUSIONS: We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCH1 genetic testing should be considered in patients with PD and a family history of DRD.

Direct genetic evidence for involvement of tau in progressive supranuclear palsy. European Study Group on Atypical Parkinsonism Consortium.

OBJECTIVE: To confirm whether a dinucleotide repeat sequence in an intron of the microtubule-associated protein tau is associated with progressive supranuclear palsy (PSP) in an independent study population and to establish an improved methodology for allelotyping. BACKGROUND: It has recently been reported that a genetic variant of tau, known as the A0 allele, was represented excessively in PSP patients when compared with control subjects. METHODS: In a multicenter study, the authors examined the allelic distribution of this dinucleotide repeat marker in a set of clinically ascertained PSP patients (n = 30), multiple system atrophy (MSA) patients (n = 35), and matched control subjects (n = 70). Individuals were allelotyped using automated analysis of fluorescently labeled PCR products. RESULTS: The A0 allele was significantly overrepresented in the PSP patients (93.3% versus 76.4%; p = 0.0067; odds ratio [OR] = 4.33; 95% confidence interval [CI], 1.36 to 13.60), but not in the MSA patients. Likewise, A0 homozygotes were overrepresented in the PSP group (86.7% versus 61.1%; p = 0.02; OR = 4.14; 95% CI, 1.19 to 14.48) compared with control subjects. CONCLUSIONS: The findings of this study, which is the largest to date, support those of a previous investigation that used pathologically confirmed PSP patients. These data provide additional strong evidence that genetic variation at or near the tau gene plays an important role in the pathogenesis of PSP.

A study of five candidate genes in Parkinson's disease and related neurodegenerative disorders. European Study Group on Atypical Parkinsonism.

OBJECTIVE: To determine whether reported genetic association of polymorphisms in the CYP2D6, CYP1A1, N-acetyltransferase 2 (NAT2), DAT1, and glutathione s-transferase M1 (GSTM1) genes with PD were evident in a population of 176 unrelated patients with sporadic PD and to extend these findings to other disease groups (familial PD [n = 30], ALS [n = 50], multiple system atrophy [n = 38], progressive supranuclear palsy [n = 35], and AD [n = 23]). METHODS: A combination of allele-specific PCR and analysis of restriction fragment length polymorphisms were performed. RESULTS: We genotyped 1,131 individuals. After matching each patient with a control subject by age, sex, ethnicity, and geographic origin, there was no association of any allele/genotype with any of the six disease groups. There was an increased frequency of NAT2 slow acetylators in the ALS group compared with controls (70% versus 50%; OR 2.33 [95% CI, 1.03 to 5.30]), but this was not significant after adjusting for multiple testing. CONCLUSIONS: This is one of the most extensive candidate gene studies performed in PD and the first time that some of these loci have been studied in multiple system atrophy and progressive supranuclear palsy. In contrast with previous studies, we found no role for these polymorphisms in the etiology of PD, ALS, multiple system atrophy, progressive supranuclear palsy, or AD.

The tau gene in progressive supranuclear palsy: exclusion of mutations in coding exons and exon 10 splice sites, and identification of a new intronic variant of the disease-associated H1 haplotype in Italian cases.

Mutations in coding exons or exon 10 5'-splice-site of the gene for microtubule-associated protein tau can cause chromosome 17-linked frontotemporal dementia and parkinsonism (FTDP-17). We sequenced the 11 coding exons plus exon-intron boundaries of the tau gene in 15 cases of progressive supranuclear palsy (PSP), and found no mutations in coding exons or exon ten 5'-splice sites. These data indicate that typical PSP is not associated with tau gene mutations similar to those causing FTDP-17. We also observed a +39deltaG base change in the intron following exon 4 in three out of 69 PSP cases (all three Italians), whereas it was not found in 150 Dutch controls and once in 112 Italian controls. The +39deltaG variant arose in the context of the PSP-associated tau H1 haplotype. Although a pathogenic role cannot be entirely excluded, +39deltaG is likely to be a rare polymorphism that may be in linkage disequilibrium with a biologically relevant locus inside or near to the tau gene.

The TOS study: can we use our patients to help improve clinical assessment?

BACKGROUND: We believe that there is a need to increase awareness, particularly among foundation year doctors, of the importance of performing a full neurological examination, including ophthalmoscopy, in medical inpatients. Following a serious unexpected incident (missed papilloedema), we implemented a multifaceted intervention, including ensuring greater availability of equipment for neurological/ ophthalmological assessment, education and curriculum redesign in two large teaching hospitals in the UK. METHODS: Following the results of our initial intervention, we introduced a patient assessment scoring system to evaluate patient recollection of the completeness of neurological examination by medical staff in the two Trusts over a four-month period. RESULTS: Of the 93 patients referred to neurology during this period, 33% could not recollect being examined with a tendon hammer and 48% said they had not been examined with an ophthalmoscope. In contrast, the majority (95.7%) remembered the use of a stethoscope in their examination. The data were fed back to medical staff which resulted in greater awareness of the importance of a complete neurological examination. No further adverse incidents of missed papilloedema were reported in the following 12 months, although it would be premature to state that this situation has been resolved. CONCLUSIONS: A patient assessment score can be used by medical staff to raise awareness of the importance of a complete neurological examination from referring physicians.

Imaging results in a consecutive series of 530 new patients in the Birmingham Headache Service.

Guidelines recommend imaging only headache patients with sinister features in the history or on examination. We prospectively collected data on imaging newly presenting patients to a UK headache service. CT and MRI results were classified as normal or showing an insignificant or significant abnormality. Over 5 years, 3,655 new patients (69% female; mean age 42.0 years) with headache disorders were seen. Five hundred thirty (14.5%) underwent imaging with large differences in the proportion referred by each consultant. There were more insignificant abnormalities on MRI (46%) than CT (28%). There were 11 significantly abnormal results (2.1% of those imaged). Significant abnormalities were found in patients diagnosed with migraine in 1.2% and in 0.9% of those with tension-type headache. Significant abnormalities in those suspected to have an intracranial abnormality occurred in 5.5%. This supports the practice of selecting patients with suspicious findings for imaging, rather than imaging all patients.

Ability of a nurse specialist to diagnose simple headache disorders compared with consultant neurologists.

OBJECTIVE: To compare the ability of a headache nurse specialist and consultant neurologists in diagnosing tension-type headache and migraine. METHODS: An experienced neurology ward sister was trained in the differential diagnosis of headache disorders. Over six months, patients with non-acute headache disorders and role players trained to present with benign or sinister headaches were seen by both the nurse and a consultant neurologist. Both reached independent diagnoses of various headache disorders. RESULTS: Consultants diagnosed 239 patients with tension-type headache (47%), migraine (39%), or other headache disorders (14%). The nurse agreed with the consultant in 92% of cases of tension-type headache, 91% of migraine, and 61% of other diagnoses. Where the nurse did not agree with the diagnosis, most would have been referred for a consultant opinion. Both the nurse and the doctors misdiagnosed the same three of 13 role players. The investigation rate of the consultants varied between 18% and 59%. Only one clinically relevant abnormality was found on head scans and this was strongly suspected clinically. CONCLUSIONS: A headache nurse specialist can be trained to diagnose tension-type headache and migraine. A nationwide nurse led diagnostic headache service could lead to substantial reduction in neurology waiting times.

Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes.

OBJECTIVE: To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism. METHODS: The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases. RESULTS: Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later. CONCLUSIONS: PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.

COMT inhibition with tolcapone does not affect carbidopa pharmacokinetics in parkinsonian patients in levodopa/carbidopa (Sinemet).

AIMS: Tolcapone is a novel catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/carbidopa or levodopa/benserazide therapy to improve treatment of Parkinson's disease. The aim of the current study was to investigate the potential effect of tolcapone on the pharmacokinetics of carbidopa. METHODS: This was an open-label study in 12 parkinsonian patients receiving optimal levodopa/carbidopa therapy and tolcapone 200 mg three times daily for 6 weeks. Blood samples were taken at baseline (i.e. before the first tolcapone intake) and after 1-2 weeks and 6 weeks so that carbidopa pharmacokinetics before and during tolcapone treatment could be assessed. RESULTS: No changes in any pharmacokinetic parameters of carbidopa were observed. The mean AUC(0,tau) and Cmax values at baseline were 0.39 microg ml-1 h and 0. 14 microg ml-1, respectively. During tolcapone treatment these values were on average 0.35 microg ml-1 h (AUC(0,tau), week 1-2), 0. 34 microg ml-1 h (AUC(0,tau), week 6 and 0.13 microg ml-1 (Cmax, weeks 1-2 and 6). tmax remained unchanged (approx. 2 h). CONCLUSIONS: These results indicate that tolcapone does not affect carbidopa elimination and that no interaction of any clinical relevance occurs between tolcapone and carbidopa.

The HhaI polymorphism in the CYP2D6 gene is not associated with Parkinson's disease in a Caucasian population.

Polymorphisms of the CYP2D6 gene have been reported in association with susceptibility to Parkinson's disease (PD). In a Japanese population, a HhaI polymorphism in the CYP2D6 gene was associated with a 5.56-fold risk of PD (Tsuneoka et al., 1993). We investigated the frequency of this polymorphism in Caucasian patients with sporadic PD and in healthy controls. Although the frequency of the polymorphism was significantly higher in Caucasians compared with Japanese, there was no association with PD.

Wilson's disease presenting in a family with an apparent dominant history of tremor.

A patient with Wilson's disease is described who presented with dystonic tremor in a family with an apparent dominant history of tremor. Subsequent investigation showed that the patient's mother had essential tremor, with molecular analysis of the ATP7B gene excluding the possibility of pseudodominant inheritance. This case highlights the importance of considering the possibility of Wilson's disease in every young patient with a movement disorder, even where the clinical picture does not suggest a recessively inherited disorder.

Two large British kindreds with familial Parkinson's disease: a clinico-pathological and genetic study.

We present the findings of a study of two large unrelated kindreds with autosomal dominant Parkinson's disease. The affected members were assessed clinically and with [(18)F]6-fluorodopa-PET and were indistinguishable from patients with the sporadic form of Parkinson's disease. In one kindred, an affected member was examined subsequently at autopsy and Lewy bodies were present in a distribution typical of sporadic Parkinson's disease. These kindreds are distinct from other Parkinsonian kindreds with identified genetic loci (PARK1-4) and provide further evidence for genetic heterogeneity in familial Parkinson's disease.