Novel clinicopathological characteristics differentiate dementia with Lewy bodies from Parkinson's disease dementia.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) known as Lewy body dementias have overlapping clinical and neuropathological features. Neuropathology in both includes combination of Lewy body and Alzheimer's disease (AD) pathology. Cerebral amyloid angiopathy (CAA), often seen in AD, is increasingly recognized for its association with dementia. AIMS: This study investigated clinical and neuropathological differences between DLB and PDD. METHODS: 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. RESULTS: CAA was more common in DLB than in PDD (P = 0.003). The severity of CAA was greater in DLB than in PDD (P = 0.009), with significantly higher CAA scores in the parietal lobe (P = 0.043), and the occipital lobe (P = 0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. CONCLUSIONS: This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD.

Review: Clinical, neuropathological and genetic features of Lewy body dementias.

Lewy body dementias are the second most common neurodegenerative dementias after Alzheimer's disease and include dementia with Lewy bodies and Parkinson's disease dementia. They share similar clinical and neuropathological features but differ in the time of dementia and parkinsonism onset. Although Lewy bodies are their main pathological hallmark, several studies have shown the emerging importance of Alzheimer's disease pathology. Clinical amyloid-ß imaging using Pittsburgh Compound B (PiB) supports neuropathological studies which found that amyloid-ß pathology is more common in dementia with Lewy bodies than in Parkinson's disease dementia. Nevertheless, other co-occurring pathologies, such as cerebral amyloid angiopathy, TDP-43 pathology and synaptic pathology may also influence the development of neurodegeneration and dementia. Recent genetic studies demonstrated an important role of APOE genotype and other genes such as GBA and SNCA which seem to be involved in the pathophysiology of Lewy body dementias. The aim of this article is to review the main clinical, neuropathological and genetic aspects of dementia with Lewy bodies and Parkinson's disease dementia. This is particularly relevant as future management for these two conditions may differ.

Exploring the putative role of kallikrein-6, calpain-1 and cathepsin-D in the proteolytic degradation of α-synuclein in multiple system atrophy.

AIMS: There is evidence that accumulation of α-synuclein (α-syn) in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) results from impaired removal of α-syn rather than its overproduction. Kallikrein-6 (KLK6), calpain-1 (CAPN1) and cathepsin-D (CTSD) are among a small number of proteases that cleave α-syn and are dysregulated in PD and DLB. Our aim in this study was to determine whether protease activity is altered in another α-synucleinopathy, multiple system atrophy (MSA), and might thereby modulate the regional distribution of α-syn accumulation. METHODS: mRNA and protein level and/or activity of KLK6, CAPN1 and CTSD were measured and assessed in relation to α-syn load in multiple brain regions (posterior frontal cortex, caudate nucleus, putamen, occipital cortex, pontine base and cerebellar white matter), in MSA (n = 20) and age-matched postmortem control tissue (n = 20). RESULTS: CTSD activity was elevated in MSA in the pontine base and cerebellar white matter. KLK6 and CAPN1 levels were elevated in MSA in the putamen and cerebellar white matter. However, the activity or level of these proteolytic enzymes did not correlate with the regional distribution of α-syn. CONCLUSIONS: Accumulation of α-syn in MSA is not due to reduced activity of the proteases we have studied. We suggest that their upregulation is likely to be a compensatory response to increased α-syn in MSA.

Histological heterogeneity in a large clinical cohort of juvenile idiopathic inflammatory myopathy: analysis by myositis autoantibody and pathological features.

AIM: Juvenile idiopathic inflammatory myopathies have been recently reclassified into clinico-serological subgroups. Myopathological correlates of the subgroups are incompletely understood. METHODS: We studied muscle biopsies from 101 children with clinically and serologically defined juvenile idiopathic inflammatory myopathies from the UK JDM Cohort and Biomarker Study by applying the international JDM score tool, myopathological review and C5b-9 complement analysis. RESULTS: Autoantibody data were available for 90/101 cases with 18/90 cases positive for anti-TIF1γ, 15/90 anti-NXP2, 11/90 anti-MDA5, 5/90 anti-Mi2 and 6/90 anti-PmScl. JDM biopsy severity scores were consistently low in the anti-MDA5 group, high in the anti-Mi2 group, and widely distributed in the other groups. Biopsies were classified histologically as perifascicular atrophy (22/101), macrophage-rich necrosis (6/101), scattered necrosis (2/101), clustered necrosis (2/101), inflammatory fibre invasion (2/101), chronic myopathic change (1/101), diffuse endomysial macrophage infiltrates (40/101) and minimal change (24/101). MDA5 cases segregated with the minimal change group and showed no capillary C5b-9-deposition. The Mi2 group displayed high severity scores and a tendency towards sarcolemmal complement deposition. NXP2 and TIF1γ groups showed a variety of pathologies with a high proportion of diffuse endomysial macrophage infiltrates and a high proportion of capillary C5b-9 deposition. CONCLUSION: We have shown that juvenile idiopathic inflammatory myopathies have a spectrum of histopathological phenotypes and show distinct complement attack complex deposition patterns. Both correlate in some cases with the serological subtypes. Most cases do not show typical histological features associated with dermatomyositis (e.g. perifascicular atrophy). In contrast, more than half show relatively mild histopathological changes.

Characteristics of progressive supranuclear palsy presenting with corticobasal syndrome: a cortical variant.

AIMS: Since the first description of the classical presentation of progressive supranuclear palsy (PSP) in 1963, now known as Richardson's syndrome (PSP-RS), several distinct clinical syndromes have been associated with PSP-tau pathology. Like other neurodegenerative disorders, the severity and distribution of phosphorylated tau pathology are closely associated with the clinical heterogeneity of PSP variants. PSP with corticobasal syndrome presentation (PSP-CBS) was reported to have more tau load in the mid-frontal and inferior-parietal cortices than in PSP-RS. However, it is uncertain if differences exist in the distribution of tau pathology in other brain regions or if the overall tau load is increased in the brains of PSP-CBS. METHODS: We sought to compare the clinical and pathological features of PSP-CBS and PSP-RS including quantitative assessment of tau load in 15 cortical, basal ganglia and cerebellar regions. RESULTS: In addition to the similar age of onset and disease duration, we demonstrated that the overall severity of tau pathology was the same between PSP-CBS and PSP-RS. We identified that there was a shift of tau burden towards the cortical regions away from the basal ganglia; supporting the notion that PSP-CBS is a 'cortical' PSP variant. PSP-CBS also had less severe neuronal loss in the dorsolateral and ventrolateral subregions of the substantia nigra and more severe microglial response in the corticospinal tract than in PSP-RS; however, neuronal loss in subthalamic nucleus was equally severe in both groups. CONCLUSIONS: A better understanding of the factors that influence the selective pathological vulnerability in different PSP variants will provide further insights into the neurodegenerative process underlying tauopathies.

Neuropathological features of multiple system atrophy with cognitive impairment.

Cognitive impairment (CI) is an exclusion criterion for the diagnosis of multiple system atrophy (MSA), according to the second consensus statement. This view was recently challenged by patients with pathologically confirmed MSA who were reported to have dementia. With an aim to investigate the pathological substrate of CI in MSA, quantitative assessment of the glial and neuronal cytoplasmic inclusions and semiquantitative assessment of neuronal loss in the cortical and limbic regions was performed. No differences in the severity of these MSA-related pathological findings were identified between nine MSA cases with CI and nine MSA cases with normal cognition. Alzheimer's-related pathological changes, cerebral amyloid angiopathy, and cerebrovascular disease did not differ between the two MSA groups. MSA-specific α-synuclein and secondary pathological conditions were not more severe in MSA cases with CI, suggesting that although CI may be intrinsic to the MSA disease process, further investigation into the pathological basis of cognitive impairment in MSA is warranted.

Pantothenate kinase-associated neurodegeneration is not a synucleinopathy.

AIMS: Mutations in the pantothenate kinase 2 gene (PANK2) are responsible for the most common type of neurodegeneration with brain iron accumulation (NBIA), known as pantothenate kinase-associated neurodegeneration (PKAN). Historically, NBIA is considered a synucleinopathy with numerous reports of NBIA cases with Lewy bodies and Lewy neurites and some cases reporting additional abnormal tau accumulation. However, clinicopathological correlations in genetically proven PKAN cases are rare. We describe the clinical, genetic and neuropathological features of three unrelated PKAN cases. METHODS: All three cases were genetically screened for the PANK2 gene mutations using standard Sanger polymerase chain reaction sequencing. A detailed neuropathological assessment of the three cases was performed using histochemical and immunohistochemical preparations. RESULTS: All cases had classical axonal swellings and Perls' positive iron deposition in the basal ganglia. In contrast to neuroaxonal dystrophies due to mutation of the phospholipase A2, group VI (PLA2G6) gene, in which Lewy body pathology is widespread, no α-synuclein accumulation was detected in any of our PKAN cases. In one case (20-year-old male) there was significant tau pathology comprising neurofibrillary tangles and neuropil threads, with very subtle tau pathology in another case. CONCLUSIONS: These findings indicate that PKAN is not a synucleinopathy and, hence the cellular pathways implicated in this disease are unlikely to be relevant for the pathomechanism of Lewy body disorders.

High resolution MR anatomy of the subthalamic nucleus: imaging at 9.4 T with histological validation.

Using conventional MRI the subthalamic nucleus (STN) is not clearly defined. Our objective was to define the anatomy of the STN using 9.4 T MRI of post mortem tissue with histological validation. Spin-echo (SE) and 3D gradient-echo (GE) images were obtained at 9.4 T in 8 post mortem tissue blocks and compared directly with corresponding histological slides prepared with Luxol Fast Blue/Cresyl Violet (LFB/CV) in 4 cases and Perl stain in 3. The variability of the STN anatomy was studied using internal reference points. The anatomy of the STN and surrounding structures was demonstrated in all three anatomical planes using 9.4 T MR images in concordance with LFB/CV stained histological sections. Signal hypointensity was seen in 6/8 cases in the anterior and medial STN that corresponded with regions of more intense Perl staining. There was significant variability in the volume, shape and location of the borders of the STN. Using 9.4 T MRI, the internal signal characteristics and borders of the STN are clearly defined and significant anatomical variability is apparent. Direct visualisation of the STN is possible using high field MRI and this is particularly relevant, given its anatomical variability, for planning deep brain stimulation.

Review: genetics and neuropathology of primary pure dystonia.

Neuropathology has been the key to understanding the aetiology of many neurological disorders such as Alzheimer's disease, Parkinson's disease, frontotemporal degeneration and cerebellar ataxias. Dystonia shares many clinical features with these conditions but research in general, has been unrewarding in providing information on disease processes. Neuropathological studies are few in number and only limited morphological abnormalities have been described. In the genetic literature, dystonia loci are represented as DYT and are assigned ascending numerals chronologically as they are identified. This review will concentrate on the neuropathology of primary pure dystonia, focusing on DYT1 and DYT6 and the correlation between clinical and genetic findings. Research in this area is incomplete and confounded by the rarity of post mortem brain tissue. However, recent findings, indicating a direct interaction between the torsinA (TOR1A) gene responsible for DYT1 and the thanatos-associated domain-containing apoptosis-associated protein 1 (THAP1) gene responsible for DYT6, have important implications in understanding these two entities and also for other members of this group of disorders.

The neuropathology, pathophysiology and genetics of multiple system atrophy.

Multiple system atrophy (MSA) is an unrelenting, sporadic, adult-onset, neurodegenerative disease of unknown aetiology. Its clinically progressive course is characterized by a variable combination of parkinsonism, cerebellar ataxia and/or autonomic dysfunction. Neuropathological examination often reveals gross abnormalities of the striatonigral and/or olivopontocerebellar systems, which upon microscopic examination are associated with severe neuronal loss, gliosis, myelin pallor and axonal degeneration. MSA is a member of a diverse group of neurodegenerative disorders termed α-synucleinopathies, due to the presence of abnormal α-synuclein positive cytoplasmic inclusions in oligodendrocytes, termed glial cytoplasmic inclusions. These are the hallmark neuropathological lesion of MSA and are thought to play a central role in the pathogenesis of the disease. In this review, neuropathological features of MSA are described in detail, along with recent advances in the pathophysiology and genetics of the disease. Our current knowledge of the expression and accumulation of α-synuclein, and efforts to model the disease in vitro and in vivo, are emphasized in this paper and have helped formulate a working hypothesis for the pathogenesis of MSA.

LRRK2 expression in idiopathic and G2019S positive Parkinson's disease subjects: a morphological and quantitative study.

AIMS: Mutations in the gene encoding leucine-rich repeat kinase-2 (LRRK2) have been established as a common genetic cause of Parkinson's disease (PD). The distribution of LRRK2 mRNA and protein in the human brain has previously been described, although it has not been reported in PD cases with the common LRRK2 G2019S mutation. METHODS: To further elucidate the role of LRRK2 in PD, we determined the localization of LRRK2 mRNA and protein in post-mortem brain tissue from control, idiopathic PD (IPD) and G2019S positive PD cases. RESULTS: Widespread neuronal expression of LRRK2 mRNA and protein was recorded and no difference was observed in the morphological localization of LRRK2 mRNA or protein between control, IPD and G2019S positive PD cases. Using quantitative real-time polymerase chain reaction, we demonstrated that there is no regional variation in LRRK2 mRNA in normal human brain, but we have identified differential expression of LRRK2 mRNA with significant reductions recorded in limbic and neocortical regions of IPD cases compared with controls. Semi-quantitative analysis of LRRK2 immunohistochemical staining demonstrated regional variation in staining intensity, with weak LRRK2 immunoreactivity consistently recorded in the striatum and substantia nigra. No clear differences were identified in LRRK2 immunoreactivity between control, IPD and G2019S positive PD cases. LRRK2 protein was identified in a small proportion of Lewy bodies. CONCLUSIONS: Our data suggest that widespread dysregulation of LRRK2 mRNA expression may contribute to the pathogenesis of IPD.

Cerebral amyloidosis: amyloid subunits, mutants and phenotypes.

Cerebral amyloid diseases are part of a complex group of chronic and progressive entities bracketed together under the common denomination of protein folding disorders and characterized by the intra- and extracellular accumulation of fibrillar aggregates. Of the more than 25 unrelated proteins known to produce amyloidosis in humans only about a third of them are associated with cerebral deposits translating in cognitive deficits, dementia, stroke, cerebellar and extrapyramidal signs, or a combination thereof. The familial forms reviewed herein, although infrequent, provide unique paradigms to examine the role of amyloid in the mechanism of disease pathogenesis and to dissect the link between vascular and parenchymal amyloid deposition and their differential contribution to neurodegeneration.

A clinico-pathological study of subtypes in Parkinson's disease.

We have carried out a systematic review of the case files of 242 donors with pathologically verified Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders in an attempt to corroborate the data-driven subtype classification proposed by Lewis and colleagues (Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005; 76: 343-8). Cases were segregated into earlier disease onset (25%), tremor dominant (31%), non-tremor dominant (36%) and rapid disease progression without dementia (8%) subgroups. We found a strong association between a non-tremor dominant disease pattern and cognitive disability. The earlier disease onset group had the longest duration to death, and greatest delay to the onset of falls and cognitive decline. Patients with a tremor dominant disease pattern did not live significantly longer than non-tremor dominant patients and showed no difference in mean time to onset of falls and hallucinations. Rapid disease progression was associated with older age, early depression and early midline motor symptoms, and in 70% of the cases, tremulous onset. The non-tremor dominant subgroup had a significantly higher mean pathological grading of cortical Lewy bodies than all other groupings (P < 0.05) and more cortical amyloid-beta plaque load and cerebral amyloid angiopathy than early disease onset and tremor dominant groups (P = 0.047). An analysis of cases with pathologically defined neocortical Lewy body disease confirmed the link between bradykinetic onset, cognitive decline and Lewy body deposition in the neocortex. Although neuropathological examination failed to distinguish the other subtypes, the classification scheme was supported by an analysis of clinical data that were independent of the basic subgroup definitions.

Cloning and sequence analysis of desmosomal glycoproteins 2 and 3 (desmocollins): cadherin-like desmosomal adhesion molecules with heterogeneous cytoplasmic domains.

Desmosomal glycoproteins 2 and 3 (dg2 and 3) or desmocollins have been implicated in desmosome adhesion. We have obtained a 5.0-kb-long clone for dg3 from a bovine nasal epidermal lambda gt11 cDNA library. Sequence analysis of this clone reveals an open reading frame of 2,517 bases encoding a polypeptide of 839 amino acids. The sequence consists of a signal peptide of 28 amino acids, a precursor sequence of 104 amino acids, and a mature protein of 707 amino acids. The latter has the characteristics of a transmembrane glycoprotein with an extracellular domain of 550 amino acids and a cytoplasmic domain of 122 amino acids. The sequence of a partial clone from the same library shows that dg2 has an alternative COOH terminus that is extended by 54 amino acids. Genomic DNA sequence data show that this arises by splicing out of a 46-bp exon that encodes the COOH-terminal 11 amino acids of dg3 and contains an in-frame stop codon. The extracellular domain of dg3 shows 39.4% protein sequence identity with bovine N-cadherin and 28.4% identity with the other major desmosomal glycoprotein, dg1, or desmoglein. The cytoplasmic domain of dg3 and the partial cytoplasmic domain of dg2 show 23 and 24% identity with bovine N-cadherin, respectively. The results support our previous model for the transmembrane organization of dg2 and 3 (Parrish, E.P., J.E. Marston, D.L. Mattey, H.R. Measures, R. Venning, and D.R. Garrod. 1990. J. Cell Sci. 96:239-248; Holton, J.L., T.P. Kenny, P.K. Legan, J.E. Collins, J.N. Keen, R. Sharma, and D.R. Garrod. 1990. J. Cell Sci. 97:239-246). They suggest that these glycoproteins are specialized for calcium-dependent adhesion in their extracellular domains and, cytoplasmically, for the molecular interactions involved in desmosome plaque formation. Moreover this represents the first example of alternative splicing within the cadherin family of cell adhesion molecules.

The bovine desmocollin family: a new gene and expression patterns reflecting epithelial cell proliferation and differentiation.

We have discovered a third bovine desmocollin gene, DSC3, and studied expression of all three desmocollin genes, DSC1, 2, and 3, by Northern blotting, RT-PCR and in situ hybridization. DSC1 is strongly expressed in epidermis and tongue papillae, showing a "skin"-type pattern resembling that previously described for keratins 1 and 10. Expression is absent from the epidermal basal layer but appears in the immediate suprabasal layers and continues uniformly to the lower granular layer. In tongue epithelium, expression is suprabasal and strictly localized to papillae, being absent from interpapillary regions. In other epithelial low level DSC1 expression is detectable only by RT-PCR. The distribution of Dsc1 glycoproteins, detected by an isoform-specific monoclonal antibody, closely reflects mRNA distribution in epidermis and tongue. DSC2 is ubiquitously expressed in epithelia and cardiac muscle. In stratified epithelia, expression appears immediately suprabasal, continuing weakly to the lower granular layer in epidermis and to just above half epithelial thickness in interpapillary tongue, oesophageal, and rumenal epithelia. DSC3 expression is restricted to the basal and immediately suprabasal layers in stratified epithelia. In deep rete ridges DSC expression strikingly resembles the distribution of stem, transit-amplifying, and terminally differentiating cells described by others. DSC3 expression is strongly basal, DSC2 is strong in 5-10 suprabasal layers, and then weakens to be superseded by strong DSC1. These results suggest that desmocollin isoform expression has important functional consequences in epithelial proliferation, stratification, and differentiation. The data also provide a standard for nomenclature of the desmocollins.

Clinical outcomes of progressive supranuclear palsy and multiple system atrophy.

Prognostic predictors have not been defined for progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Subtypes of both disorders have been proposed on the basis of early clinical features. We performed a retrospective chart review to investigate the natural history of pathologically confirmed cases of PSP and MSA. Survival data and several clinically relevant milestones, namely: frequent falling, cognitive disability, unintelligible speech, severe dysphagia, dependence on wheelchair for mobility, the use of urinary catheters and placement in residential care were determined. On the basis of early symptoms, we subdivided cases with PSP into 'Richardson's syndrome' (RS) and 'PSP-parkinsonism' (PSP-P). Cases of MSA were subdivided according to the presence or absence of early autonomic failure. Sixty-nine (62.7%) of the 110 PSP cases were classified as RS and 29 (26.4%) as PSP-P. Of the 83 cases of MSA, 42 (53.2%) had autonomic failure within 2 years of disease onset. Patients with PSP had an older age of onset (P < 0.001), but similar disease duration to those with MSA. Patients with PSP reached their first clinical milestone earlier than patients with MSA (P < 0.001). Regular falls (P < 0.001), unintelligible speech (P = 0.04) and cognitive impairment (P = 0.03) also occurred earlier in PSP than in MSA. In PSP an RS phenotype, male gender, older age of onset and a short interval from disease onset to reaching the first clinical milestone were all independent predictors of shorter disease duration to death. Patients with RS also reached clinical milestones after a shorter interval from disease onset, compared to patients with PSP-P. In MSA early autonomic failure, female gender, older age of onset, a short interval from disease onset to reaching the first clinical milestone and not being admitted to residential care were independent factors predicting shorter disease duration until death. The time to the first clinical milestone is a useful prognostic predictor for survival. We confirm that RS had a less favourable course than PSP-P, and that early autonomic failure in MSA is associated with shorter survival.

Expression of BRI2 mRNA and protein in normal human brain and familial British dementia: its relevance to the pathogenesis of disease.

INTRODUCTION: Two different disease-specific mutations in the BRI2 gene, situated on chromosome 13, have been identified as giving rise to familial British dementia (FBD) and familial Danish dementia (FDD). Each mutation results in extension of the open reading frame generating the disease-specific precursor proteins which are cleaved by furin-like proteolysis releasing the amyloidogenic C-terminal peptides ABri and ADan in FBD and FDD, respectively. MATERIAL AND METHODS: To understand the mechanism of the formation of amyloid lesions in FBD, we studied the origin of the precursor proteins and furin in the human brain. We used control brains, cases of sporadic Alzheimer's disease (AD), variant AD with cotton wool plaques and FBD to study BRI2 mRNA expression using in situ hybridization. Furin and BRI2 protein expression was investigated using Western blotting and immunohistochemistry. RESULTS: BRI2 mRNA and BRI2 protein are widely expressed primarily by neurones and glia and are deposited in the amyloid lesions in FBD. They were, however, not expressed by cerebrovascular components. Furin expression showed a similar pattern except that it was also present in cerebrovascular smooth muscle cells. CONCLUSIONS: These findings suggest that neurones and glia and are a major source of BRI2 protein and that in FBD, the mutated precursor protein may undergo furin cleavage within neurones to produce the amyloid peptide ABri. The failure to demonstrate BRI2 in blood vessels under the conditions tested suggests that vascular amyloid peptide production does not contribute significantly to cerebral amyloid angiopathy (CAA) in FBD and FDD, lending indirect support to the drainage hypothesis of CAA.

The use of nerve and muscle biopsy in the diagnosis of vasculitis: a 5 year retrospective study.

INTRODUCTION: Peripheral nerve vasculitis is an important condition which can be diagnostically challenging and is one of the principal current indications for nerve and muscle biopsy. Previous studies have suggested that combined nerve and muscle biopsy (usually of the superficial peroneal nerve and peroneus brevis muscle) produces a higher diagnostic yield than nerve biopsy alone in the investigation of vasculitis. OBJECTIVE: To determine whether in our two centres combined nerve (usually the sural) and muscle (usually the vastus lateralis) biopsy improved diagnostic yield compared with nerve biopsy alone. METHODS: We interrogated our database of all nerve biopsies (usually of the sural nerve) performed at our institutions over 5 years and identified 53 cases of biopsy proven peripheral nerve vasculitis. Clinicopathological and neurophysiological data in these patients were reviewed. RESULTS: The most common clinical presentation was with a painful asymmetric axonal polyneuropathy or mononeuritis multiplex (66% of cases). Nerve biopsy demonstrated definite vasculitis in 36%, probable vasculitis in 62% and no vasculitis in 2% of cases. In 24 patients a muscle biopsy (usually the vastus lateralis) was also performed and vasculitis was demonstrated in 46% of these (in 13% showing definite and 33% probable vasculitis). There was only one patient in whom vasculitis was demonstrated in muscle but not in peripheral nerve. CONCLUSION: Combined nerve (usually sural) and vastus lateralis muscle biopsy did not significantly increase the diagnostic yield compared with nerve biopsy alone. A sensible approach to the diagnosis of peripheral nerve vasculitis is to choose a nerve to biopsy which is clinically affected and amenable to biopsy. If the sural nerve is chosen, the data suggest that it is not routinely worth doing a vastus lateralis biopsy at the same time, whereas if the superficial peroneal nerve is chosen, it seems appropriate to do a combined superficial peroneal nerve and peroneus brevis biopsy. It is still not known if both the sural and superficial peroneal nerves are involved clinically which one gives the higher yield if biopsied.