Identifying co-morbidities and risk in people with epilepsy: The Maltese experience.

BACKGROUND: People with epilepsy are at increased risk of multiple co-morbidities that may influence risk of adverse outcomes including impact on quality of life and premature mortality. These risk factors include potentially modifiable clinical characteristics associated with sudden unexpected death in epilepsy (SUDEP). For services to tackle risk, the clinical complexity of the target epilepsy population needs to be defined. While this has been comprehensively studied in large, economically developed countries little knowledge of these issues exist in small economically developed countries, like Malta (population: 500,000). METHODS: This was a single centre study focused exclusively on patients attending Gozo General Hospital (GGH) Malta. STROBE guidance for reporting cross sectional studies was used to design and report the study. This was a retrospective review of standard care and SUDEP and seizure risks provided to all adults (over 18 years) with epilepsy attending GGH (2018-2021). RESULTS: The review identified 68 people and 92% were compliant with their anti-seizure medication. A fifth (21%) had an intellectual disability. Despite only one patient having a psychotic illness, 19% were on antipsychotic medication. Only 18% of patients had a specific epilepsy care plan, 6% nocturnal surveillance and none had received advice on SUDEP. DISCUSSION: Patient outcomes may be improved with increasing rates of personalized epilepsy care plans, appropriate nocturnal surveillance and reducing the prescription of antipsychotic medication as it is associated with greater risk of mortality. Issues such as stigma and shame appear to play a significant role in small communities and their access to care.

Amantadine toxicity causing visual hallucinations.

Amantadine is an N-methyl-d-aspartate receptor agonist with secondary dopaminergic activity that is used to treat Parkinson's disease-related dyskinesia and to treat fatigue in multiple sclerosis. It is primarily renally excreted and so impaired kidney function prolongs its half-life and may lead to toxicity. We describe a woman with multiple sclerosis taking amantadine who developed acute renal impairment, which triggered florid visual hallucinations that resolved on stopping the medication.

Genetic landscape of ALS in Malta based on a quinquennial analysis.

Genetic risk for amyotrophic lateral sclerosis (ALS) is highly elevated in genetic isolates, like the island population of Malta in the south of Europe, providing a unique opportunity to investigate the genetics of this disease. Here we characterize the clinical phenotype and genetic profile of the largest series of Maltese ALS patients to date identified throughout a 5-year window. Cases and controls underwent neuromuscular assessment and analysis of rare variants in ALS causative or risk genes following whole-genome sequencing. Potentially damaging variants or repeat expansions were identified in more than 45% of all patients. The most commonly affected genes were ALS2, DAO, SETX and SPG11, an infrequent cause of ALS in Europeans. We also confirmed a significant association between ATXN1 intermediate repeats and increased disease risk. Damaging variants in major ALS genes C9orf72, SOD1, TARDBP and FUS were however either absent or rare in Maltese ALS patients. Overall, our study underscores a population that is an outlier within Europe and one that represents a high percentage of genetically explained cases.

Progressive encephalomyelitis with rigidity and myoclonus (PERM).

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a subtype of stiff-person syndrome (formerly stiff-man syndrome). It is rare and disabling, and characterised by brainstem symptoms, muscle stiffness, breathing issues and autonomic dysfunction. We describe a 65-year-old man who presented with odynophagia together with tongue and neck swelling, followed by multiple cranial nerve palsies culminating in bilateral vocal cord paralysis with acute stridor. He subsequently developed progressive generalised hypertonia and painful limb spasms. Serum antiglycine receptor antibody was strongly positive, but antiglutamic acid decarboxylase and other antibodies relating to stiff-person syndrome were negative. We diagnosed PERM and gave intravenous corticosteroids and immunoglobulins without benefit; however, following plasma exchange he has made a sustained improvement.

SOD1 D91A variant in the southernmost tip of Europe: a heterozygous ALS patient resident on the island of Gozo.

Amyotrophic lateral sclerosis (ALS) is frequently caused by mutations in the SOD1 gene. Here, we report the first SOD1 variant in Malta, an archipelago of three inhabited islands in southern Europe. We describe a patient with a sporadic form of ALS living on the island of Gozo in which the heterozygous SOD1 c.272A>C; p.(Asp91Ala) variant was detected. The patient had a late onset (79 years), sensory impairments and rapid disease progression culminating in respiratory failure. ALS has not yet developed in any of the three additional family members in which the D91A variant was identified. None of the healthy controls from the Maltese population were found to carry this variant. This report underscores the high prevalence of the D91A variant in Europe, despite the presence of a North-South gradient in its frequency, and confirms that this variant can be associated with dominant cases in Mediterranean countries.

Occupation and amyotrophic lateral sclerosis risk: a case-control study in the isolated island population of Malta.

Objective: Amyotrophic lateral sclerosis (ALS) is a mostly sporadic neurodegenerative disease. The role of environmental factors has been extensively investigated but associations remain controversial. Considering that a substantial proportion of adult life is spent at work, identifying occupations and work-related exposures is considered an effective way to detect factors that increase ALS risk. This process may be further facilitated in population isolates due to environmental and genetic homogeneity. Our study investigated occupations and occupational exposures potentially associated with ALS risk in the isolated island population of Malta, using a case-control study design. Methods: Patients with ALS and randomly identified matched controls (1:1) were recruited throughout a four-year window, from 2017 through 2020. Data on educational level, residence, main occupation, smoking, and alcohol history were collected. Results: We found that compared to controls (44.4%), a higher percentage (73.7%) of ALS patients reported a blue-collar job as their main occupation (OR 2.04, 95% CI 1.2-3.72; p = 0.0072). Through regression analysis, craft and related trades occupations such as carpentry and construction (ISCO-08 major group 7), were found to be positively associated with ALS, with patients in this occupational category found to be more prone to develop bulbar-onset ALS (p = 0.0297). Overall, patients with ALS reported a significantly higher exposure to work-related strenuous physical activity (OR 2.35, 95% CI 1.53-3.59; p = 0.0002). Conclusion: Our findings suggest that manual workers particularly those working in the carpentry and construction industries have an increased ALS risk, possibly due to a history of intense or sustained physical activity.

Eslicarbazepine acetate response in intellectual disability population versus general population.

BACKGROUND: A quarter of people with intellectual disability (ID) have epilepsy, compared to approximately one in a hundred across the general population. Evidence for the safe and effective prescribing of antiepileptic drugs (AEDs) for those with ID is, however, limited. AIMS OF STUDY: This study seeks to strengthen the research evidence around Eslicarbazepine Acetate (ESL), a new AED, by comparing response of individuals with ID to those from the general population who do not have ID. METHODS: A single data set was created through retrospective data collection from English and Welsh NHS Trusts. The UK-based Epilepsy Database Research Register (Ep-ID) data collection and analysis method were used. RESULTS: Data were collected for 93 people (36 ID and 57 'no ID'). Seizure improvement of '>50%' was higher at 12 months for 'no ID' participants (56%), compared to ID participants (35%). Retention rates were slightly higher for those with ID (56% compared to 53%). Neither difference was significant. CONCLUSIONS: Tolerance and Efficacy for ID and 'no ID' people in our data set were similar. Seizure improvement and retention rates were slightly lower than that found in other European data sets, but findings strengthen the evidence for the use of ESL in the ID population.

Lacosamide in the general population and in people with intellectual disability: Similar responses?

PURPOSE: Epilepsy prevalence is significantly higher in people with Intellectual Disability (ID) compared to people with epilepsy (PWE) from the general population. Increased psychological and behavioural problems, healthcare costs, morbidity, mortality and treatment resistance to antiepileptic drugs (AEDs) is associated with epilepsy in ID populations. Prescribing AEDs for PWE and ID is challenging and influenced heavily by studies conducted with the general population. Our study compares Lacosamide (LCM) response for the ID population to those from the general population; using data from an UK based epilepsy database register (EP ID/PDD AED Register). METHODS: Pooled retrospective case notes data for PWE prescribed LCM at 11 UK NHS Trusts were analysed. Participants were classified as per WHO guidance into groups of moderate-profound ID, mild ID and General population. Demographics, concomitant AEDs, starting and maximum dosage, exposure length, adverse effects, dropout rates, seizure frequency were collected. Group differences were reported as odds ratios estimated from univariable logistic regression models. RESULTS: Of 232 consented participants, 156 were from the general population and 76 had ID (24 mild, 52 moderate-profound). Twelve month withdrawal rates and reasons, efficacy, side-effects, start and maximum doses were similar between the groups. Dose titration between baseline and three months was significantly slower in the ID group (p = 0.02). CONCLUSION: There were no differences for LCM outcomes between general and ID groups. Slower LCM titration in ID populations in the first 3 months was associated with higher retention and lower behavioural side effects as compared to similar European studies.

A subarachnoid haemorrhage-specific outcome tool.

Functional outcome after subarachnoid haemorrhage has traditionally been assessed using scales developed for other neurological conditions. The modified Rankin score and Glasgow Outcome Scale are most commonly used. Employment of these scales in subarachnoid haemorrhage is hampered by well recognized limitations. We set out to develop and validate a new condition-specific subarachnoid haemorrhage outcome tool (SAHOT). Items addressing diverse aspects of the impact of subarachnoid haemorrhage were collected during focus groups involving patients, next-of-kin and multidisciplinary professionals involved in subarachnoid haemorrhage management. After a series of iterative revisions, the resultant questionnaire was applied to patients and their next-of-kin at 1, 3 and 6 months post-subarachnoid haemorrhage. Rasch methodology was used to finalize the structure of the questionnaire and explore the extent to which SAHOT scores met Rasch-based criteria of successful measurement. The SAHOT was further assessed using traditional scale evaluation techniques, and validated in a second separate subarachnoid haemorrhage patient cohort. The final SAHOT included 56 items dealing with cognitive, physical, and behavioural/psychological consequences of subarachnoid haemorrhage. Rasch analysis indicated the scale successfully measured functional outcome post-subarachnoid haemorrhage. Three item scoring categories produced the best scale performance. There was no evidence of differential item functioning between patients and next-of-kin. The SAHOT was found to be acceptable, have good convergent and divergent validity, good discrimination and excellent responsiveness. It was successfully validated in a second subarachnoid haemorrhage patient cohort. The SAHOT offers the first subarachnoid haemorrhage-specific scientifically robust outcome measure with potential utility in neurovascular clinical services and research studies.

Neurosarcoidosis associated with intracerebral haemorrhage: a challenge in diagnosis and management.

Sarcoidosis is an idiopathic multisystem granulomatous disorder of unknown cause. Nervous system involvement (central and/or peripheral) is uncommon, developing in 5%-10%. The presenting symptoms are variable, reflecting the level of involvement, and frequently fluctuate and progress. Diagnosing neurosarcoidosis in people with previously confirmed systemic disease may be relatively straightforward, but diagnosing primary neurosarcoidosis is challenging. Managing neurosarcoidosis is primarily consensus based; corticosteroid is its mainstay, alongside corticosteroid-sparing agents and emerging novel therapies. We describe a 39-year-old woman who presented with cranial neuropathy. Serial imaging, cerebrospinal fluid sampling and tissue biopsy gave a diagnosis of probable neurosarcoidosis. Her clinical course was complicated by intracerebral haemorrhage following intravenous corticosteroids for neurological relapse. This is a very rare complication of neurosarcoidosis; we discuss its possible causes and suggest ways to reduce its risk.

Acute respiratory distress syndrome following alemtuzumab therapy for relapsing multiple sclerosis.

We present the case of a 54 year old woman with known relapsing-remitting multiple sclerosis who presented with acute respiratory deterioration five weeks after a first course of alemtuzumab. Imaging showed bilateral ground glass changes and extensive investigations confirmed chest infection with dual pathogens - Pneumocystis jirovecii and Cytomegalovirus. She responded to standard anti-PJP and CMV therapy and was discharged on oral prophylaxis. Opportunistic infections in the weeks immediately following alemtuzumab therapy remain an uncommon complication but one that requires clinical vigilance, careful monitoring and appropriate prophylactic therapy.

Perampanel in the general population and in people with intellectual disability: Differing responses.

PURPOSE: There is a shortfall of suitably powered studies to provide evidence for safe prescribing of AEDs to people with Intellectual Disability (ID). We report clinically useful information on differences in response to Perampanel (PER) adjunctive treatment for refractory epilepsy between ID sub-groups and general population from the UK Ep-ID Research Register. METHOD: Pooled retrospective case notes data of consented people with epilepsy (PWE) prescribed PER from 6 UK centres was classified as per WHO guidance into groups of moderate -profound ID, mild ID and General population. Demographics, concomitant AEDs, starting and maximum dosage, exposure length, adverse effects, dropout rates, seizure type and frequency were collected. Group differences were reported as odds ratios estimated from univariable logistic regression models. RESULTS: Of the 144 PWE (General population 71, Mild ID 48, Moderate to profound ID 48) examined the association between withdrawal and ID type was marginally statistically significant (p=0.07). Moderate to profound ID PWE were less likely to come off PER compared to mild ID (OR=0.19, CI=0.04-0.92, p=0.04). Differences in mental health side effects by groups was marginally statistically significant (p=0.06). Over 50% seizure improvement was seen in 11% of General population, 24% mild ID and 26% Moderate to profound ID. CONCLUSIONS: PER seems safe in PWE with ID. It is better tolerated by PWE with Moderate to profound ID than PWE with higher functioning. Caution is advised when history of mental health problems is present. The standardised approach of the Ep-ID register UK used confirms that responses to AEDs by different ID groups vary between themselves and General population.

A community study in Cornwall UK of sudden unexpected death in epilepsy (SUDEP) in a 9-year population sample.

PURPOSE: Epilepsy-related death, particularly sudden unexpected death in epilepsy (SUDEP), is underestimated by healthcare professionals. One argument that physicians use to justify the failure to discuss SUDEP with patients and their families is that there is a lack of evidence for any protective interventions. However, there is growing evidence of potentially modifiable risk factors for SUDEP; although large-scale trials of interventions are still lacking. We determined the main risk factors associated with SUDEP in a comprehensive community sample of epilepsy deaths in Cornwall UK from 2004 to 2012. METHODS: We systemically inspected 93 cases of all epilepsy and epilepsy associated deaths which occurred in Cornwall between 2004 and 2012 made available to us by the HM Cornwall coroner. These are the deaths where epilepsy was a primary or a secondary cause. RESULTS: 48 cases met the criteria for SUDEP and we elicited associated relevant risk factors. Many findings from our study are comparable to what has been reported previously. New points such as most of the population had increase in either or both seizure frequency/intensity within six months of death and majority did not have an epilepsy specialist review in the last one year to demise were noted. CONCLUSION: This study is the first epidemiological study in England occurring in a whole population identifying systemically all deaths and the first large scale review in UK of SUDEP deaths since 2005. Being a community based study a key issue which was highlighted was that in the SUDEPs examined many might have been potentially preventable.

A new clinical variant of the post-malaria neurological syndrome.

Post-malaria neurological syndrome (PMNS) is an uncommon, monophasic illness that occurs within two months following recovery from Plasmodium falciparum (Pf) malaria. Clinical manifestations of PMNS are variable, but published cases uniformly feature neurological and/or psychiatric symptoms without long tract signs. We describe a case of severe brainstem and spinal cord inflammation with paraplegia and sphincter involvement in a 48 year old woman following recovery from a Pf malarial illness. We propose that this case represents a previously unreported form of PMNS, which has features that distinguish it from acute disseminated encephalomyelitis, and that the recognised clinical spectrum of PMNS should be extended to include brainstem and spinal cord inflammation.