Neurology

Parkinson's families project: a UK-wide study of early onset and familial Parkinson's disease (2024)

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Type of publication:

Journal article

Author(s):

Fang Z.-H.; Tan M.M.X.; Schmaderer T.M.; Stafford E.J.; Pollard M.; Tilney R.; Hodgson M.; Wu L.; Labrum R.; Hehir J.; Polke J.; Lange L.M.; Schapira A.H.V.; Bhatia K.P.; Hartley L.; Nacorda A.; Gentilini I.; Wales E.; Amar K.; Tuck S.; Raw J.; Crouch R.; Walker R.; Hand A.; Strens L.; Sveinbjornsdottir S.; Webster G.; Williams S.; Schrag A.; Nath U.; Mann C.; D'Costa D.; Barnes C.; Jones E.; Slaght S.J.; Wiblin L.; Archibald N.; *Capps E.; Jones S.; Sophia R.; Vickers C.; Dean S.; Truscott R.; Sheridan R.; Brierley C.; Kunc M.; Funaki A.; Asad S.; Tai Y.; Chaudhuri R.; Guptha S.; Cosgrove J.; Misbahuddin A.; Padiachy D.; Paviour D.; Bandmann O.; Buccoliero R.; Wickremaratchi M.; Gregory R.; Molloy S.; Shaik S.; Arianayagam S.; Saifee T.; Wakeman E.; Towns C.; Jasaityte S.; Jarman P.R.; Singleton A.B.; Blauwendraat C.; Klein C.; Houlden H.; Wood N.W.; Morris H.R.; Real R.

Citation:

npj Parkinson's Disease. 10(1) (no pagination), 2024. Article Number: 188. Date of Publication: December 2024.

Abstract:

The Parkinson's Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson's disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset <=45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruited affected and unaffected relatives. We analysed DNA samples with a combination of single nucleotide polymorphism (SNP) array genotyping, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing (WGS). We investigated the association between identified pathogenic mutations and demographic and clinical factors such as age at motor symptom onset, family history, motor symptoms (MDS-UPDRS) and cognitive performance (MoCA). We performed baseline genetic analysis in 718 families, of which 205 had sporadic early-onset PD (sEOPD), 113 had familial early-onset PD (fEOPD), and 400 had late-onset familial PD (fLOPD). 69 (9.6%) of these families carried pathogenic variants in known monogenic PD-related genes. The rate of a molecular diagnosis increased to 28.1% in PD with motor onset <=35 years. We identified pathogenic variants in LRRK2 in 4.2% of families, and biallelic pathogenic variants in PRKN in 3.6% of families. We also identified two families with SNCA duplications and three families with a pathogenic repeat expansion in ATXN2, as well as single families with pathogenic variants in VCP, PINK1, PNPLA6, PLA2G6, SPG7, GCH1, and RAB32. An additional 73 (10.2%) families were carriers of at least one pathogenic or risk GBA1 variant. Most early-onset and familial PD cases do not have a known genetic cause, indicating that there are likely to be further monogenic causes for PD.

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Upskilling and Implementing splinting into Occupational Therapy (OT) inpatient therapy for Neurological patients (2024)

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Type of publication:

Service improvement case study

Author(s):

*Chelsea Hamer

Citation:

SaTH Improvement Hub, July 2024

Abstract:

Increase the number of patients who have early management splinting intervention by 45%, by 2nd September 2024. Evidenced through caseload audit.

Link to PDF poster

Regression of a spinal schwannoma after Pomalidomide (2023)

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Type of publication:
Journal article

Author(s):
Kunnel Jomon, Mathew; Pepper, Joshua; *O'Connor, Nigel; Price, Rupert

Citation:
British Journal of Neurosurgery. 37(4):954-955, 2023 Aug

Abstract:
A 77-year old female with a history of neurofibromatosis type 2 (NF2) was diagnosed with a spinal schwannoma that was managed conservatively over a decade. During this time, follow up imaging revealed this lesion had been growing and the patient had become symptomatic from it necessitating surgical decompression. However, the patient had been diagnosed with multiple myeloma and underwent treatment with Pomalidomide chemotherapy which delayed surgery for the spinal schwannoma. Further imaging of the spine revealed significant regression in the size of the spinal schwannoma. This phenomenon has not peviously been reported and this report aims to explore the implications of Pomalidomide in patients with NF2 related spinal schwannomas.

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Correlation of Pathological Findings with MRI Imaging in Traumatic Spinal Cord Injury in the Hyperacute Timeframe in a Nonhuman Primate Model (2023)

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Type of publication:
Conference abstract

Author(s):
*Fayez O.; Simmons H.; Johnson K.; Schalk D.; Brunner K.; Basu P.; Capuano S.; Nesathurai S.

Citation:
Journal of Neuropathology and Experimental Neurology. Conference: 99th Annual Meeting of the American Association of Neuropathologists, AANP 2023. Monterey, CA United States. 82(6) (pp 502), 2023. Date of Publication: June 2023.

Abstract:
Background: Traumatic Spinal Cord Injury (TSCI) remains a significant cause of morbidity and mortality in humans. Magnetic Resonance Imaging (MRI) has been a spectacular modality in management, however, data correlating MRI findings with pathological insults in the hyperacute time-frame (i.e., within one hour of injury) is limited. This is due to the time-period between injury and transport to hospital is typically one-hour or more. Only after assessment and stabilization can an MRI be completed. In this context, nonhuman primate models are essential to provide insights into this critical scientific hypothesis. Method(s): The subject was a Rhesus macaque. Baseline MRI imaging of the spine was obtained. A small laminotomy was performed at L5 level and an epidural balloon catheter was advanced to the level of the lower thoracic spine which was inflated rapidly and remained for one-hour to produce lesions consistent with TSCI. MRI imaging, with and without contrast, was obtained over the next hour. Subsequently, the subject was humanely euthanized and a post-mortem examination was conducted. Tissue sections were collected from the epicenter, caudal and cephalad sites of the lesion. Result(s): The abnormalities were most prominent with Disco- Lava sequence MRI Technique. Sagittal images of the thoracic spine displayed increased abnormalities including increased signal intensity. The findings were consistent with edema and/or hemorrhage. Histology of coronal sections at the level of injury revealed focally extensive disruption of grey matter and central canal with marked grey matter hemorrhage, acute necrosis, and mild multifocal white matter hemorrhage. Eosinophilic material and erythrocytes were found in adjacent sections, up to 2 cm caudal to the lesion. Conclusion(s): MRI abnormalities were present within one hour after injury in acute experimental spinal cord injury. The histopathological findings are consistent with the radiological abnormalities.

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Adult North Star Network (ANSN): Consensus Guideline For The Standard Of Care Of Adults With Duchenne Muscular Dystrophy (2021)

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Type of publication:
Journal article

Author(s):
Quinlivan, R; Messer, B; Murphy, P; Astin, R; Mukherjee, R; Khan, J; Emmanuel, A; Wong, S C; Kulshresha, R; Willis, T; Pattni, J; *Willis, D; Morgan, A; Savvatis, K; Keen, R; Bourke, J; Marini Bettolo, C; Hewamadduma, C; ANSN

Citation:
Journal of Neuromuscular Diseases; Sep 2021 [epub ahead of print]

Abstract:
There are growing numbers of adults with Duchenne Muscular Dystrophy living well into their fourth decade. These patients have complex medical needs that to date have not been addressed in the International standards of care. We sought to create a consensus based standard of care through a series of multi-disciplinary workshops with specialists from a wide range of clinical areas: Neurology, Cardiology, Respiratory Medicine, Gastroenterology, Endocrinology, Palliative Care Medicine, Rehabilitation, Renal, Anaesthetics and Clinical Psychology. Detailed reports of evidence reviewed and the consensus building process were produced following each workshop and condensed into this final document which was approved by all members of the Adult North Star Network including service users. The aim of this document is to provide a framework to improve clinical services and multi-disciplinary care for adults living with Duchenne Muscular Dystrophy.

An unusual presentation of dysarthria in a young patient, a stroke mimic (2021)

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Type of publication:
Journal article

Author(s):
*Simpson D.; *David O.; Nasr F

Citation:
Acute Medicine; Jun 2021; vol. 20 (no. 2); p. 140-143

Abstract:
Internal carotid artery dissection commonly affects younger patients. We present a case of a previously fit and well 43-year-old gentleman who presented with a sudden onset of slurring of speech, with right-sided tongue deviation and fasciculation on examination. Signs and symptoms began following participation in a home workout class. Magnetic resonance angiography revealed right-sided extracrainal internal carotid artery dissection leading to right-sided unilateral twelfth cranial nerve palsy.

Supratentorial vs infratentorial posterior calvarial distraction osteogenesis for the increase of ICV in children with syndromic or multi-suture craniosynostosis: a retrospective cohort study (2021)

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Type of publication:
Journal article

Author(s):
Sharman J.; Rodrigues D.; McGuirk S.; *Panikkar M.; Nishikawa H.; Dover S.; Evans M.; White N.

Citation:
Child's Nervous System; 2021 [epub ahead of print]

Abstract:
Purpose: Craniosynostosis is the premature and pathological fusion of calvarial sutures. One modality of surgical treatment of syndromic craniosynostosis is posterior calvarial distraction (PCD). This can be either supratentorial or infratentorial. Currently, supratentorial PCD may be regarded as safer but produces a smaller increase in calvarial volume compared to infratentorial PCD. This study quantifies and compares the effectiveness of supratentorial and infratentorial PCD to help guide surgical decision-making. Method(s): The CT and/or MRI scans of 47 cases of craniosynostosis who underwent PCD from the Birmingham Children's Hospital (BCH) were converted to sagittal series multi-planar reformatted (MPR) scans for the manual calculation of ICV. The 47 cases were classified as having undergone either supratentorial or infratentorial PCD using lateral plain film radiographs, with 28 and 32 pairs of pre- and post-operative CT/MRI scans reviewed respectively. Result(s): A statistically significant difference between supratentorial and infratentorial PCD was observed for the increase in supratentorial volume (STV) (P = 0.0458) and total intracranial volume (TICV) (P = 0.0437), but not for the increase in infratentorial volume (ITV) (P = 0.0697). The relationship for each volume trended towards convergence but was not achieved before the physical limit of 30 mm distraction had been reached. Intraclass correlation coefficient values for agreement of MRI and CT scans for STV, ITV and total ICV were 0.852, 0.864 and 0.854 respectively. Conclusion(s): Our evidence suggests that supratentorial PCD is more effective for increasing ICV in a clinical setting. CT and MRI imaging modalities are acceptably clinically interchangeable for calculating ICV in craniosynostosis.

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Benign thyroid swelling presenting as Horner's syndrome (2020)

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Type of publication:
Journal article

Author(s):
*Shaji S.K.; *Chan J.; *Hari C

Citation:
BMJ Case Reports; Dec 2020; vol. 13 (no. 12).

Abstract:
Horner's syndrome is a rare neurological condition seen in association with the disruption in the sympathetic nerve supply. Thyroid swelling is a common condition but rarely causes cervical sympathetic chain compression. We describe a case of a 54-year-old man who presented with Horner's syndrome secondary to a benign thyroid nodule with pressure effect on the sympathetic chain. An association between thyroid pathologies and Horner's syndrome has been mentioned previously, however, to our knowledge, this is the first case of Horner's syndrome being the initial presentation for an underlying benign thyroid swelling.

Link to full-text [NHS OpenAthens account required]

The Cortical Basal ganglia Functional Scale (CBFS): Development and preliminary validation (2020)

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Type of publication:
Journal article

Author(s):
Lang A.E.; Stebbins G.T.; Wang P.; Boxer A.L.; Jabbari E.; Morris H.; Lamb R.; Boxer (PI) A.; Boeve B.; Dickerson B.; Grossman M.; Litvan I.; Ljubenkov P.; Rojas-Martinez J.; Pantelyat A.; Tartaglia M.-C.; Wills A.-M.; Morris (PI) H.; Amar K.; *Capps E.; Carey G.; Church A.; Critchley P.; Ghosh B.; Houlden H.; Hu M.; Kobylecki C.; Massey L.; Molloy S.; Nath U.; Pavese N.; Rowe J.B.

Citation:
Parkinsonism and Related Disorders; Oct 2020; vol. 79 ; p. 121-126

Abstract:
Objective: To develop a patient/care-giver reported scale capable of easily and reliably assessing functional disability in 4 repeat tauopathies (4RTs). Background(s): 4R tauopathies including progressive supranuclear palsy, corticobasal degeneration and a subset of frontotemporal dementias manifest a range of overlapping clinical phenotypes. No available rating scale is capable of evaluating the functional impact of these complex disorders. Method(s): A multi-staged modified Delphi process was used to propose, evaluate and rank potential scale items providing content validity ratios. Staged cognitive pretesting involving input from examiners, patients and caregivers was followed by validation testing in patients participating in the 4R Tauopathy Neuroimaging Initiative or the PROgressive Supranuclear Palsy CorTico-Basal Syndrome MSA Longitudinal Study. Clinimetric properties were examined using classical test theory and item response methods, assessing data quality, reliability, construct validity, convergent validity and known-group validity. Result(s): The resultant Cortical Basal ganglia Functional Scale (CBFS) included questions on Motor Experiences in Daily Living (14 items) and Non-Motor Experiences of Daily Living (17 items). Reliability was acceptable for internal consistency, test-retest stability, item discrimination, item-scaling thresholds and item-fit. Examination of construct validity revealed a parsimonious two-factor solution, and concurrent validity demonstrated significant correlations between the CBFS and other measures of disease severity and functional impairment. The CBFS significantly discriminated between all diagnostic groups and controls (all AUCs>90). The CBFS scores demonstrated sensitivity to change over a 12 month follow-up in patients with probable 4RTs. Conclusion(s): The CBFS is a patient/care-giver reported outcome measure with excellent clinimetric properties that captures disability correlated with motor, cognitive and psychiatric impairments.

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Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome (2019)

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Type of publication:
Journal article

Author(s):
Jabbari E, Holland N, Chelban V, Jones PS, Lamb R, Rawlinson C, Guo T, Costantini AA, Tan MMX, Heslegrave AJ, Roncaroli F, Klein JC, Ansorge O, Allinson KSJ, Jaunmuktane Z, Holton JL, Revesz T, Warner TT, Lees AJ, Zetterberg H, Russell LL, Bocchetta M, Rohrer JD, Williams NM, Grosset DG, Burn DJ, Pavese N, Gerhard A, Kobylecki C, Leigh PN, Church A, Hu MTM, Woodside J, Houlden H, Rowe JB, Morris HR.

Patients at Shrewsbury and Telford Hospital NHS Trust were recruited into this study.

Citation:
JAMA Neurol. 2019 Dec 20 [Epub ahead of print]

Abstract:
IMPORTANCE:
Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied.

OBJECTIVE:
To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD.

DESIGN, SETTING, PARTICIPANTS:
This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019.

MAIN OUTCOMES AND MEASURES:
Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures.

RESULTS:
A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05).

CONCLUSIONS AND RELEVANCE:
These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.

Full-text available [Open access - no password required]

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