Not a benign motor neuron disease: longitudinal imaging captures relentless motor connectome disintegration in primary lateral sclerosis.

BACKGROUND AND PURPOSE: Primary lateral sclerosis (PLS) is a progressive upper motor neuron disorder associated with considerable clinical disability. Symptoms are typically exclusively linked to primary motor cortex degeneration and the contribution of pre-motor, supplementary motor, cortico-medullary and inter-hemispheric connectivity alterations are less well characterized. METHODS: In a single-centre, prospective, longitudinal neuroimaging study 41 patients with PLS were investigated. Patients underwent standardized neuroimaging, genetic profiling with whole exome sequencing, and comprehensive clinical assessments including upper motor neuron scores, tapping rates, mirror movements, spasticity assessment, cognitive screening and evaluation for pseudobulbar affect. Longitudinal neuroimaging data from 108 healthy controls were used for image interpretation. A standardized imaging protocol was implemented including 3D T1-weighted structural, diffusion tensor imaging and resting-state functional magnetic resonance imaging. Following somatotopic segmentation, cortical thickness analyses, probabilistic tractography, blood oxygenation level dependent signal analyses and brainstem volumetry were conducted to evaluate cortical, brainstem, cortico-medullary and inter-hemispheric connectivity alterations both cross-sectionally and longitudinally. RESULTS: Our data confirm progressive primary motor cortex degeneration, considerable supplementary motor and pre-motor area involvement, progressive brainstem atrophy, cortico-medullary and inter-hemispheric disconnection, and close associations between clinical upper motor neuron scores and somatotopic connectivity indices in PLS. DISCUSSION: Primary lateral sclerosis is associated with relentlessly progressive motor connectome degeneration. Clinical disability in PLS is likely to stem from a combination of intra- and inter-hemispheric connectivity decline and primary, pre- and supplementary motor cortex degeneration. Simple 'bedside' clinical tools, such as tapping rates, are excellent proxies of the integrity of the relevant fibres of the contralateral corticospinal tract.

Morbihan Syndrome, a UK Case Series.

PURPOSE: To describe 10 patients with Morbihan syndrome, a rare condition characterized by the slow appearance of erythema and solid edema on the upper portion of the face, and review the literature. METHODS: Retrospective case series and review. RESULTS: The majority of patients were male (80%), and the mean age at presentation was 67 years (range, 48-88 years); 60% had asymmetrical disease (affecting mainly the right side). All subjects underwent a lid biopsy to support the diagnosis of Morbihan syndrome, which showed features of inflammation and vascular dysfunction, highly suggestive of a rosacea histological picture complicated by chronic lymphoedema. A range of medical and surgical treatment were used with variable success. The most effective ones included oral isotretinoin, intralesional triamcinolone injections, and debulking surgery. CONCLUSIONS: Morbihan syndrome is a rare and chronic condition. It can be difficult to treat and may require a range of interventions.

Stenotrophomonas maltophilia-A Case Series of a Rare Keratitis Affecting Patients With Bandage Contact Lens.

OBJECTIVES: Stenotrophomonas maltophilia is an opportunistic pathogen known to form biofilms on contact lens and case surfaces that may result in permanent visual loss in cases of microbial keratitis. Because of its multiple drug resistance and extremely low incidence, there is little consensus on treatment. We investigated the predisposing factors, management, and visual outcomes in a small case series of patients to better inform the management of this rarely reported keratitis. METHODS: Retrospective analysis of medical records was performed at a single tertiary referral center between 2011 and 2017. The case notes of each microbiology confirmed S. maltophilia keratitis were examined. RESULTS: Six cases were identified (four men) with a median age of 62 years (range 1 month-90 years) and pre-existing ocular surface disease in all cases. At presentation, four patients were using bandage contact lenses and three were on topical antibiotic and steroid medications. Initial antibiotic treatment was intensive topical 0.3% ofloxacin and 5% cefuroxime, which was modified based on corneal scrape culture and sensitivity and clinical findings. One patient chose not to complete the treatment course. The 5 remaining patients had complete resolution of ulceration over a mean of 2.9 months (SD 0.8 months). CONCLUSIONS: Contact lens in the context of ocular surface problems, prolonged topical antibiotic and steroid treatments may predispose to S. maltophilia, a rare cause of keratitis. We report successful treatment with case-specific combinations of topical antibiotics such as fluoroquinolone, cotrimoxazole, and/or cephalosporin agents, although visual outcomes remain poor due to corneal scar.

Validation of CADS Grading Scale: An Ophthalmic Specific Grading Instrument for Facial Nerve Palsy.

PURPOSE: To evaluate the inter- and intraobserver reliability of the CADS score, a previously described facial nerve grading instrument for ophthalmic grading of facial nerve palsy. METHODS: This is a cross-sectional validation study. Two clinicians independently assessed and graded each patient on the same day, masked to each other's grading. Four parameters are assessed in the CADS scale: Cornea (0-3, ±a), static Asymmetry (0-2), Dynamic function (0-3), and Synkinesis (0-2). One clinician reassessed the patients and performed the grading again at a minimum time interval of 1 hour later. A weighted κ analysis was performed to determine inter- and intraobserver reliability using 95% bootstrapped bias-corrected and accelerated (BCa) confidence intervals (CIs). RESULTS: Thirty-three patients (27 women, mean age 51.7, range 23-80 years) with unilateral facial nerve palsy were graded. The overall interobserver reliability was 0.80 (95% BCa CI: 0.68-0.91) for cornea, 0.93 for resting asymmetry (95% BCa CI: 0.55-1.00), 0.80 for dynamic function (95% BCa CI: 0.50-0.96), and 0.88 (95% BCa CI: 0.71-0.96) for synkinesis. The overall intraobserver reliability was 0.93 for cornea (95% BCa CI: 0.83-0.98), 0.82 for resting asymmetry (95% BCa CI: 0.53-0.96), 0.92 for dynamic function (95% BCa CI: 0.72-1.00), and 0.98 for synkinesis (95% BCa CI: 0.84-1.00). CONCLUSION: The CADS grading scale demonstrates good interobserver reliability and very good intraobserver reliability. It incorporates all ophthalmic complications for facial nerve palsy and remains easy to use and refer to.

Periorbital Autologous Fat Grafting in Facial Nerve Palsy.

PURPOSE: To report outcomes and complications of periorbital autologous fat grafting (AFG) in improving volume loss-related symmetry and function in facial nerve palsy patients and to assess patient satisfaction. METHODS: A retrospective, noncomparative review of all facial nerve palsy patients who underwent periorbital AFG at single center over a 4-year period. Two independent graders objectively assessed standard photographs for any change in volume loss and symmetry: pre- and postoperative periods (early, 0-2 months; intermediate, 3-9 months; and late, >10 months). Any adverse outcomes were recorded. Patient satisfaction was assessed by questionnaire survey. RESULTS: A total of 18 facial nerve palsy patients (13 females) underwent periorbital AFG between February 2011 and 2015. Mean age was 51.9 ± 15.3 years (range, 26-76). Mean follow up was 6.8 ± 4.6 (range, 0.5-15) months. Photographs of 14 patients were eligible for evaluation. Tear trough visibility (p < 0.01), infraorbital rim visibility (p = 0.03), and lower eyelid-cheek junction symmetry (p < 0.01) improved in the early postoperative period with persistence of improvement in the latter parameter at intermediate postoperative period (p < 0.01). Lagophthalmos significantly improved (p = 0.03) in the early postoperative period. Two patients developed cheek cellulitis and 4 had persistent malar edema (3 had existing edema). Questionnaire survey showed a reduction in daytime ocular lubricants and an improvement in nocturnal-lagophthalmos symptoms. CONCLUSION: Periorbital AFG is a useful adjunct in improving symmetry and lagophthalmos in facial nerve palsy patients where volume loss is a contributory factor but effects were not long lasting. Patient satisfaction is high. Those with preexisting malar bags are at higher risk of developing persistent malar edema following periorbital AFG.

Clinical Outcomes of Ruptured Periorbital and Orbital Dermoid Cysts.

PURPOSE: To evaluate the clinical outcomes of ruptured dermoid cysts. METHODS: A multicenter, retrospective study of all cases of periorbital and orbital dermoid cysts with histopathological evidence of rupture, including those with clinical rupture, was performed over a 10-year period. Demographics and clinical outcomes of ruptured dermoid cysts were recorded. Persistent inflammation was defined as the presence of edema, erythema, and discomfort for at least 28 days. RESULTS: Eighty-six cases of dermoid cysts were identified. Median age was 5.5 (range, 1-63) years. Location of cyst was either periorbital (n = 60, 70%) or orbital (n = 26, 30%). There were 29 cases with clinically apparent rupture: 27 surgically ruptured (93%) and 2 spontaneous rupture (7%). Persistent inflammation was found in 1 spontaneous cyst rupture case (50%) and 1 surgically ruptured cyst (3.7%). Older age (p = 0.01) and bony attachment (p = 0.001) were significant factors for cyst rupture, while there was no influence from cyst location (p = 0.14). CONCLUSIONS: Persistent inflammation is uncommon after surgical rupture of dermoid cysts, but likely after spontaneous rupture. Older age and bony attachment are risk factors for cyst rupture.

How can we maximize the use of our operating lists? An analysis of factors influencing theatre efficiency in oculoplastic day surgery.

Operating theatre utilization has become the principal measure of NHS operating theatre service performance. We analysed data from oculoplastic theatres in a tertiary centre to identify factors influencing theatre efficiency. We conducted three audits on operating theatre utilization in 2011, 2014 and 2015. Data was collected from real time information entered into the hospital database, including time of arrival, induction, first cut and close of operation. The primary outcome measure was the operating list utilization rate, a combined value of anaesthetic and surgical time as a proportion of the total planned session time. The initial 2011 audit recorded an operating list utilization rate of 81.2%. However, this dropped to 64.5% in 2014 following new management and a move to a new theatre suite. Analysis of the factors contributing to poor theatre efficiency led to changes that streamlined the patient pathway, including standardized case scheduling and reducing staggered patient arrival. A 2015 reaudit analyzing the effects of these changes demonstrated an increase in the operating list utilization rate to 78%. It was significantly higher (p < 0.01) for whole-day lists (85%) compared to half-day lists (75%), suggesting that whole-day lists were more efficient. Operating theatres are a valuable resource and the factors affecting theatre efficiency within our unit are common and will be relevant to units elsewhere. Correcting them can lead to significant improvements in patient care. Data from this study may provide a benchmark for other units in the United Kingdom.

Lower Macular Pigment Optical Density in Foveal-Involved Glaucoma.

PURPOSE: To evaluate the relationship between macular pigment optical density (MPOD) and structural parameters of the macula and optic nerve head in glaucomatous eyes. DESIGN: A cross-sectional analysis of the baseline data collected during the Macular Pigment and Glaucoma Trial (ISRCTN registry number: 56985060). PARTICIPANTS: Eighty-eight subjects (48 male, 40 female) with a diagnosis of open-angle glaucoma and a median age of 67 years (interquartile range, 13; range, 36-84 years) were enrolled in this trial. METHODS: The MPOD at 0.25°, 0.5°, and 1° retinal eccentricity was measured using a customized heterochromatic flicker photometry technique. Glaucoma-related structural parameters were captured using RTVue Fourier-domain optical coherence tomography (FD-OCT). Statistical significance was set at P < 0.01, and P values ranging from 0.01 to 0.05 were considered borderline significant. MAIN OUTCOME MEASURES: The MPOD and its relationship to the macula and optic nerve head topography in glaucomatous eyes. RESULTS: The MPOD peaked centrally at 0.25° of retinal eccentricity (mean ± standard deviation, 0.23±0.14) and decreased at more peripheral eccentricities. For the overall group, borderline significant correlations were observed between MPOD and a range of topographic measures, including inferior peripapillary retinal nerve fiber layer (RNFL) thickness, inferior ganglion cell complex (GCC) thickness, foveal inner retinal thickness, cup-to-disc area ratio, and optic disc rim area. Glaucomatous eyes with GCC loss involving the foveal zone on FD-OCT imaging (n = 52) had lower MPOD at 0.25°, 0.5°, and 1° of retinal eccentricity compared with those without foveal GCC involvement (P < 0.001, for all). Those with foveal GCC loss also had greater glaucoma severity, and this was evident by lower GCC and RNFL thickness, greater cup-to-disc area ratio, and lower optic disc rim area (P < 0.001 for all). CONCLUSIONS: Our observations indicate that MPOD is lower in glaucomatous eyes with foveal GCC involvement relative to those without foveal involvement. A longitudinal evaluation of MPOD and structural change among patients with glaucoma is required to elucidate the nature of any causal relationship that might exist between MPOD and foveal damage in glaucoma.

Limbic Network and Papez Circuit Involvement in ALS: Imaging and Clinical Profiles in GGGGCC Hexanucleotide Carriers in C9orf72 and C9orf72-Negative Patients.

Background: While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods: A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72. A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results: Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72-positive ALS patients. Conclusions: Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype.

Radiological correlates of pseudobulbar affect: Corticobulbar and cerebellar components in primary lateral sclerosis.

INTRODUCTION: Pseudobulbar affect (PBA) is a distressing symptom of a multitude of neurological conditions affecting patients with a rage of neuroinflammatory, neurovascular and neurodegenerative conditions. It manifests in disproportionate emotional responses to minimal or no contextual stimulus. It has considerable quality of life implications and treatment can be challenging. METHODS: A prospective multimodal neuroimaging study was conducted to explore the neuroanatomical underpinnings of PBA in patients with primary lateral sclerosis (PLS). All participants underwent whole genome sequencing and screening for C9orf72 hexanucleotide repeat expansions, a comprehensive neurological assessment, neuropsychological screening (ECAS, HADS, FrSBe) and PBA was evaluated by the emotional lability questionnaire. Structural, diffusivity and functional MRI data were systematically evaluated in whole-brain (WB) data-driven and region of interest (ROI) hypothesis-driven analyses. In ROI analyses, functional and structural corticobulbar connectivity and cerebello-medullary connectivity alterations were evaluated separately. RESULTS: Our data-driven whole-brain analyses revealed associations between PBA and white matter degeneration in descending corticobulbar as well as in commissural tracts. In our hypothesis-driven analyses, PBA was associated with increased right corticobulbar tract RD (p = 0.006) and decreased FA (p = 0.026). The left-hemispheric corticobulbar tract, as well as functional connectivity, showed similar tendencies. While uncorrected p-maps revealed both voxelwise and ROI trends for associations between PBA and cerebellar measures, these did not reach significance to unequivocally support the "cerebellar hypothesis". CONCLUSIONS: Our data confirm associations between cortex-brainstem disconnection and the clinical severity of PBA. While our findings may be disease-specific, they are consistent with the classical cortico-medullary model of pseudobulbar affect.

Brainstem-cortex disconnection in amyotrophic lateral sclerosis: bulbar impairment, genotype associations, asymptomatic changes and biomarker opportunities.

BACKGROUND: Bulbar dysfunction is a cardinal feature of ALS with important quality of life and management implications. The objective of this study is the longitudinal evaluation of a large panel imaging metrics pertaining to bulbar dysfunction, encompassing cortical measures, structural and functional cortico-medullary connectivity indices and brainstem metrics. METHODS: A standardised, multimodal imaging protocol was implemented with clinical and genetic profiling to systematically appraise the biomarker potential of specific metrics. A total of 198 patients with ALS and 108 healthy controls were included. RESULTS: Longitudinal analyses revealed progressive structural and functional disconnection between the motor cortex and the brainstem over time. Cortical thickness reduction was an early feature on cross-sectional analyses with limited further progression on longitudinal follow-up. Receiver operating characteristic analyses of the panel of MR metrics confirmed the discriminatory potential of bulbar imaging measures between patients and controls and area-under-the-curve values increased significantly on longitudinal follow-up. C9orf72 carriers exhibited lower brainstem volumes, lower cortico-medullary structural connectivity and faster cortical thinning. Sporadic patients without bulbar symptoms, already exhibit significant brainstem and cortico-medullary connectivity alterations. DISCUSSION: Our results indicate that ALS is associated with multi-level integrity change from cortex to brainstem. The demonstration of significant corticobulbar alterations in patients without bulbar symptoms confirms considerable presymptomatic disease burden in sporadic ALS. The systematic assessment of radiological measures in a single-centre academic study helps to appraise the diagnostic and monitoring utility of specific measures for future clinical and clinical trial applications.

Transconjunctival versus transcutaneous local anaesthetic administration for lower eyelid surgery: a randomised controlled trial.

AIM: To compare the associated discomfort and safety between transcutaneous (Tskin) and transconjunctival (Tconj) approaches of local anaesthetic (LA) administration in lower eyelid surgery. METHODS: A prospective randomised controlled trial comparing Tskin and Tconj LA in patients undergoing bilateral lower eyelid surgeries for horizontal laxity. Patients were randomised to receive LA via Tskin to one side and Tconj to the fellow side. LA injection was administered in a slow fashion accompanied by distraction (tapping of patient's forehead). Self-reported discomfort from the injections was rated using a 0-10 numerical rating scale. A single blinded assessor graded photographs for eyelid bruising (0 = absent, 1 = mild, 2 = moderate, 3 = severe). RESULTS: A total of 30 patients (mean age ± SD, 75.9 ± 6.7 years) were enrolled. The overall pain score (mean ± SD) was statistically lower for the Tconj than the Tskin group (3.90 ± 2.28 versus 5.33 ± 2.23, p = 0.017). More patients in the Tconj group reported substantially less pain (score of ≤3) in comparison to the Tskin group (56.7% versus 23.3%, p = 0.017). In individual patients, the Tconj pain score was found to be significantly lower than the Tskin side (p = 0.008). Bruising scores were higher in the Tskin group, but this was not statistically significant (p = 0.13). No other adverse effects were found. CONCLUSION: Tconj delivery of LA in lower eyelids with horizontal laxity is safe and associated with less discomfort and bruising than the conventional Tskin route. TRIAL REGISTRATION NUMBER: NCT04102878.

Lower eyelid involutional entropion following cataract surgery.

OBJECTIVES: To determine whether cataract surgery is associated with an increased risk of subsequent lower eyelid entropion and evaluate potential associated factors. METHODS: This retrospective cohort study included consecutive patients undergoing first eye cataract surgery over a 10-year period at a single institution (n = 14,574). The fellow phakic eye served as control. Patient records were evaluated up until either the time of second eye cataract surgery or any other intraocular or adnexal surgery. The primary outcome was the rate of entropion repair in both the pseudophakic (exposed) group and the phakic control group. Groups were compared using relative risk and Kaplan-Meier analysis. Multivariate logistic regression was used to compare pre-specified characteristics of those patients that underwent entropion repair in their pseudophakic eye with those that did not. RESULTS: A fourfold higher relative risk of undergoing entropion repair was observed in eyes that had undergone cataract surgery compared with the fellow unoperated eye (95% confidence interval 1.6-9.8; P < 0.001) with an increased risk at all timepoints between 1 and 12 years according to Kaplan-Meier analysis (P = 0.001). Median time to entropion repair after cataract surgery was 58 months (range 3-124). Documented intraoperative patient factors such as patient or eye movement, eyelid squeezing, pain or anxiety were an independent risk factor for subsequent entropion (P < 0.0001). CONCLUSIONS: Cataract surgery is associated with an increased risk of subsequent lower eyelid entropion. Surgeons should be aware of this risk in the pre- and post-operative assessment of patients undergoing cataract surgery.

Cerebellar degeneration in primary lateral sclerosis: an under-recognized facet of PLS.

While primary lateral sclerosis (PLS) has traditionally been regarded as a pure upper motor neuron disorder, recent clinical, neuroimaging and postmortem studies have confirmed significant extra-motor involvement. Sporadic reports have indicated that in addition to the motor cortex and corticospinal tracts, the cerebellum may also be affected in PLS. Cerebellar manifestations are difficult to ascertain in PLS as the clinical picture is dominated by widespread upper motor neuron signs. The likely contribution of cerebellar dysfunction to gait disturbance, falls, pseudobulbar affect and dysarthria may be overlooked in the context of progressive spasticity. The objective of this study is the comprehensive characterization of cerebellar gray and white matter degeneration in PLS using multiparametric quantitative neuroimaging methods to systematically evaluate each cerebellar lobule and peduncle. Forty-two patients with PLS and 117 demographically-matched healthy controls were enrolled in a prospective MRI study. Complementary volumetric and voxelwise analyses revealed focal cerebellar alterations instead of global cerebellar atrophy. Bilateral gray matter volume reductions were observed in lobules III, IV and VIIb. Significant diffusivity alterations within the superior cerebellar peduncle indicate disruption of the main cerebellar outflow tracts. These findings suggest that the considerable intra-cerebellar disease-burden is coupled with concomitant cerebro-cerebellar connectivity disruptions. While cerebellar dysfunction is challenging to demonstrate clinically, cerebellar pathology is likely to be a significant contributor to disability in PLS.

Macular Pigment Response to Lutein, Zeaxanthin, and Meso-zeaxanthin Supplementation in Open-Angle Glaucoma: A Randomized Controlled Trial.

Purpose: To evaluate macular pigment response to carotenoid supplementation in glaucomatous eyes. Design: Double-masked, randomized, placebo-controlled clinical trial, the European Nutrition in Glaucoma Management Study (ClinicalTrials.gov identifier, NCT04460365). Participants: Sixty-two participants (38 men, 24 women) with a diagnosis of open-angle glaucoma were enrolled. Forty-two were randomized to receive the active supplement, 20 participants were allocated to placebo. Methods: Macular pigment optical density (MPOD) was measured by autofluorescence using the Heidelberg Spectralis scanning laser ophthalmoscope. Macular pigment optical density volume within the central 6° of retinal eccentricity as well as MPOD at 0.23°, 0.51°, 0.74°, and 1.02° were recorded at baseline and at 6-month intervals over 18 months. Visual function was assessed using visual acuity, mesopic and photopic contrast sensitivity under glare conditions, photo stress recovery time, microperimetry, and Glaucoma Activities Limitation 9 questionnaire. Advanced glaucoma module scans of retinal nerve fiber layer thickness and ganglion cell complex thickness over the central 6° of retinal eccentricity also were completed at each study visit. Main Outcome Measures: Change in MPOD after supplementation with 10 mg lutein, 2 mg zeaxanthin, and 10 mg meso-zeaxanthin or placebo over 18 months. Results: A mixed-model repeated measures analysis of variance revealed a statistically significant increase in MPOD volume (significant time effect: F(3,111) = 89.31, mean square error (MSE) = 1656.9; P < 0.01). Post hoc t tests revealed a significant difference in MPOD volume at each study visit for the treatment group (P < 0.01 for all), but no change in the placebo group (P > 0.05 for all). A statistically significant increase in mesopic contrast sensitivity under glare conditions was noted at 18 months in the treatment group, but not placebo. No other structural or functional changes were observed. No serious adverse events were noted during the trial. Conclusions: Macular pigment can be augmented in glaucomatous eyes by supplementation with a formulation containing the carotenoids lutein, zeaxanthin, and meso-zeaxanthin. The greatest relative benefit was observed in those with the lowest baseline levels, but increases were noted across all participants and each retinal eccentricity. The potential benefits of MP augmentation for macular health in glaucoma merit further long-term evaluation.

Frontotemporal Pathology in Motor Neuron Disease Phenotypes: Insights From Neuroimaging.

Frontotemporal involvement has been extensively investigated in amyotrophic lateral sclerosis (ALS) but remains relatively poorly characterized in other motor neuron disease (MND) phenotypes such as primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA), post poliomyelitis syndrome (PPS), and hereditary spastic paraplegia (HSP). This review focuses on insights from structural, metabolic, and functional neuroimaging studies that have advanced our understanding of extra-motor disease burden in these phenotypes. The imaging literature is limited in the majority of these conditions and frontotemporal involvement has been primarily evaluated by neuropsychology and post mortem studies. Existing imaging studies reveal that frontotemporal degeneration can be readily detected in ALS and PLS, varying degree of frontotemporal pathology may be captured in PMA, SBMA, and HSP, SMA exhibits cerebral involvement without regional predilection, and there is limited evidence for cerebral changes in PPS. Our review confirms the heterogeneity extra-motor pathology across the spectrum of MNDs and highlights the role of neuroimaging in characterizing anatomical patterns of disease burden in vivo. Despite the contribution of neuroimaging to MND research, sample size limitations, inclusion bias, attrition rates in longitudinal studies, and methodological constraints need to be carefully considered. Frontotemporal involvement is a quintessential clinical facet of MND which has important implications for screening practices, individualized management strategies, participation in clinical trials, caregiver burden, and resource allocation. The academic relevance of imaging frontotemporal pathology in MND spans from the identification of genetic variants, through the ascertainment of presymptomatic changes to the design of future epidemiology studies.

The imaging signature of C9orf72 hexanucleotide repeat expansions: implications for clinical trials and therapy development.

While C9orf72-specific imaging signatures have been proposed by both ALS and FTD research groups and considerable presymptomatic alterations have also been confirmed in young mutation carriers, considerable inconsistencies exist in the literature. Accordingly, a systematic review of C9orf72-imaging studies has been performed to identify consensus findings, stereotyped shortcomings, and unique contributions to outline future directions. A formal literature review was conducted according to the STROBE guidelines. All identified papers were individually reviewed for sample size, choice of controls, study design, imaging modalities, statistical models, clinical profiling, and identified genotype-associated pathological patterns. A total of 74 imaging papers were systematically reviewed. ALS patients with GGGGCC repeat expansions exhibit relatively limited motor cortex involvement and widespread extra-motor pathology. C9orf72 positive FTD patients often show preferential posterior involvement. Reports of thalamic involvement are relatively consistent across the various phenotypes. Asymptomatic hexanucleotide repeat carriers often exhibit structural and functional changes decades prior to symptom onset. Common shortcomings included sample size limitations, lack of disease-controls, limited clinical profiling, lack of genetic testing in healthy controls, and absence of post mortem validation. There is a striking paucity of longitudinal studies and existing presymptomatic studies have not evaluated the predictive value of radiological changes with regard to age of onset and phenoconversion. With the advent of antisense oligonucleotide therapies, the meticulous characterisation of C9orf72-associated changes has gained practical relevance. Neuroimaging offers non-invasive biomarkers for future clinical trials, presymptomatic ascertainment, diagnostic and prognostic applications.