A Cross-sectional Study by the Italian DAISY Network

[Posted 18/May/2022]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability.

BACKGROUND: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability.

DETAILS: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3).

Copyright © American Academy of Neurology. All Rights Reserved.

Source: Rossi, S., Rubegni, A., Riso, V., et al. (2022). Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network. Neuro Genetics. 2022; 8(2): e664. Published: April, 2022. DOI: 10.1212/NXG.0000000000000664.

[Posted 19/Aug/2026]

AUDIENCE: Nephrology, Endocrinology, Emergency Medicine

KEY FINDINGS: Current safeguards for severe hyponatremia remain warranted despite recent evidence questioning restrictive correction limits. Correction should be particularly cautious in patients with sodium ≤105 mmol/L or other ODS risk factors. Frequent serum sodium measurement and urine-output monitoring are essential because spontaneous water diuresis can cause rapid sodium increases. Desmopressin may help prevent or reverse excessive correction.

BACKGROUND: Severe hyponatremia can cause life-threatening neurologic complications, while overly rapid correction can result in osmotic demyelination syndrome (ODS). Recent retrospective evidence has questioned whether existing correction limits are overly restrictive. This review reassesses the evidence supporting current treatment safeguards and emphasizes continued caution when correcting severe hyponatremia.

DETAILS: The review examines the evidence underlying international recommendations for limiting the rate of serum sodium correction, with particular attention to patients with severe or chronic hyponatremia. The authors discuss evidence linking rapid correction with ODS and review data that have challenged the need for conservative correction limits.

For chronically hyponatremic patients with serum sodium ≤120 mmol/L who are at normal risk for ODS, the US/Irish expert panel recommends limiting correction to 10–12 mmol/L during any 24-hour period and 18 mmol/L during any 48-hour period, with a minimum correction of 4–8 mmol/L. Patients at increased risk of ODS—including those with sodium ≤105 mmol/L, alcohol use disorder, hypokalemia, malnutrition, or advanced liver disease—should have correction limited to 8 mmol/L in any 24-hour period, with a minimum daily correction goal of 4–6 mmol/L.

For patients with severe symptoms, European and US/Irish recommendations support bolus administration of hypertonic saline to increase serum sodium by approximately 5 mmol/L or 4–6 mmol/L, respectively, within a few hours. The review notes that this initial increase can substantially reduce intracranial pressure and may reverse impending brain herniation.

The review concludes that current safeguards for treating severe hyponatremia should not be abandoned. Excessive increases in serum sodium can occur because of sudden elimination of dilute urine rather than excessive saline administration. Water diuresis may increase serum sodium by more than 2 mmol/L per hour, emphasizing the need for frequent serum sodium measurements and close monitoring of urine output in patients with sodium ≤120 mmol/L.

Desmopressin can be used to prevent or reverse inadvertent overcorrection. A strategy involving scheduled desmopressin with controlled hypertonic saline administration, termed the "DDAVP clamp"", has been reported to help achieve correction targets, although comparative evidence remains limited.

The review highlights that patients with sodium ≤105 mmol/L and additional risk factors for ODS are particularly vulnerable. If correction exceeds 8 mmol/L in less than 24 hours in these high-risk patients, relowering the serum sodium should be considered.

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Source: Sterns, R. H., Rondon-Berrios, H., Adrogué, H. J., et al. Treatment Guidelines for Hyponatremia: Stay the Course. Clinical Journal of the American Society of Nephrology. 2026; 19(1): 129-135. Published: January, 2024. DOI: 10.2215/CJN.0000000000000244.

A population-based cohort study in Sweden and Norway.

[Posted 17/Aug/2026]

AUDIENCE: Neurology, Psychiatry

KEY FINDINGS: In this large Nordic population-based cohort, paternal valproate monotherapy during spermatogenesis was not significantly associated with neurodevelopmental disorders in offspring compared with paternal lamotrigine or levetiracetam monotherapy. Findings were consistent across dose-response analyses and among fathers with epilepsy. The results do not support an increased neurodevelopmental risk from paternal valproate exposure, although limitations inherent to registry-based observational research remain.

BACKGROUND: Valproate is an effective antiseizure medication, but its established teratogenic effects with maternal exposure have led to regulatory restrictions for women of reproductive potential. Concerns about possible paternal effects on offspring neurodevelopment have also prompted precautionary recommendations for men. This study evaluated whether paternal valproate use during spermatogenesis was associated with neurodevelopmental disorders (NDDs) in offspring.

DETAILS: This population-based cohort study used nationwide Swedish and Norwegian health registries. It included singleton live births at >=22 completed gestational weeks between 1 January 2007 and 31 December 2020 in Sweden and between 1 January 2010 and 31 December 2018 in Norway. After exclusions, 4681 children in Sweden and 1572 children in Norway were included for analysis.

The analysis compared children whose fathers received valproate monotherapy during spermatogenesis with children whose fathers received lamotrigine or levetiracetam monotherapy. Outcomes included NDDs, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disability (ID), and disorders of psychological development. Analyses were adjusted for relevant parental and child characteristics, including parental age, psychiatric diagnoses, psychotropic medication use, epilepsy diagnosis, and, in Sweden, parental education and maternal cohabitation/marital status.

The study specifically examined paternal antiseizure medication exposure during spermatogenesis, corresponding to the approximately 3 months before conception. Dose-response analyses and analyses restricted to fathers with epilepsy were also conducted.

Among the children included in the primary comparison, 2051 were born to fathers who used valproate monotherapy during spermatogenesis. No significant association was identified between paternal valproate exposure and NDDs compared with paternal lamotrigine or levetiracetam exposure. The findings remained consistent in dose-response analyses and when the analysis was restricted to fathers with epilepsy.

During follow-up in Sweden, 406 children were diagnosed with an NDD, including 287 with ADHD, 140 with ASD, 55 with ID, and 79 with disorders of psychological development. In Norway, 60 children were diagnosed with an NDD, including 35 with ADHD, 13 with ASD, 5 with ID, and 26 with disorders of psychological development.

For ASD, the pooled adjusted hazard ratio was 1.29 (95% CI 0.89 to 1.85). The study authors noted that point estimates were slightly above 1.0 in some analyses but did not reach statistical significance.

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Source: Razaz, N., Soderling, J., Tomson, T., et al. Risk of Neurodevelopmental Disorders Associated With Paternal Use of Valproate During Spermatogenesis. Journal of Neurology, Neurosurgery & Psychiatry. 2026; 97-8: 671-679. Published: August, 2026. DOI: 10.1136/jnnp-2025-337441.

[Posted 23/Jul/2026]

AUDIENCE: Neurology, Psychiatry

KEY FINDINGS: Older adults experience a significantly elevated risk of suicide during the first year after receiving a dementia diagnosis, particularly within the first 90 days. Individuals aged 65-74 years and those diagnosed with frontotemporal dementia represent the highest-risk groups. Coexisting mental illness, substance use disorders, chronic pain, rural residence, and recent mental health service utilization further increase suicide risk. These findings support routine suicide risk assessment, early psychiatric evaluation when appropriate, caregiver support, and discussions regarding restriction of access to lethal means immediately after a dementia diagnosis.

BACKGROUND: A new diagnosis of Alzheimer's disease or related dementias (ADRD) can be psychologically distressing and may increase vulnerability to suicidal behavior. Previous studies have reported inconsistent findings regarding suicide risk after dementia diagnosis. This nationwide U.S. cohort study evaluated suicide mortality and non-fatal suicidal events during the first year following a new ADRD diagnosis and identified patient characteristics associated with increased risk.

DETAILS: This retrospective cohort study included 2,667,987 Medicare fee-for-service beneficiaries aged >=65 years with newly diagnosed ADRD identified between 2012 and 2015. Patients were followed for up to 12 months after the initial dementia diagnosis or until death. Suicide deaths were identified through linkage with the National Death Index, while non-fatal suicidal events were captured using hospital claims. Standardized mortality ratios (SMRs) compared suicide risk with that of the general U.S. older adult population. Adjusted hazard ratios (AHRs) were calculated after controlling for age, sex, and race/ethnicity. During the first year after diagnosis, 705 suicide deaths occurred, corresponding to a suicide rate of 26.42 per 100,000 person-years, with an overall SMR of 1.53 (95% CI 1.42-1.65) compared with the general older adult population. The highest relative risk was observed among adults aged 65-74 years (SMR 3.40; 95% CI 2.94-3.86), and approximately half of all suicides occurred within the first 90 days after diagnosis. Patients with frontotemporal dementia had the highest suicide rate (124.63 per 100,000 person-years) and a significantly increased risk of suicide compared with unspecified dementia (AHR 2.91; 95% CI 1.67-5.05). Rural residence, recent mental health disorders, substance use disorders, chronic pain, and recent mental health-related healthcare utilization were independently associated with higher suicide risk. Non-fatal suicidal events were more frequent among patients with vascular dementia, personality disorders, bipolar disorder, anxiety disorders, substance use disorders, and chronic pain.

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Source: Schmutte, T., Olfson, M., Maust, D. T., et al. Suicide Risk in First Year Following Dementia Diagnosis in Older Adults. Alzheimer's & Dementia. Published: May 25, 2021. DOI: 10.1002/alz.12390.

[Posted 10/Jul/2026]

AUDIENCE: Infectious Disease, Internal Medicine

KEY FINDINGS: Early initiation of a 5-day oral ensitrelvir regimen within 72 hours after symptom onset in an index patient significantly reduced the risk of developing Covid-19 among household contacts while maintaining a safety profile comparable to placebo. Clinical benefit was observed across major patient subgroups, including individuals at increased risk for severe disease, and treatment was associated with reduced household transmission. These findings support ensitrelvir as an effective postexposure prophylactic option for household contacts and suggest potential utility in other high-risk exposure settings where rapid outbreak control is needed.

BACKGROUND: Household transmission remains a major contributor to the spread of SARS-CoV-2, particularly among individuals at increased risk for severe Covid-19. Although vaccination and prior infection have reduced disease severity, waning immunity and emerging variants continue to sustain transmission. Previous trials evaluating oral antiviral agents for postexposure prophylaxis in household contacts have not demonstrated significant protection, highlighting the need for effective preventive therapies. This phase 3 trial evaluated whether oral ensitrelvir, a SARS-CoV-2 3C-like protease inhibitor, could prevent Covid-19 among household contacts exposed to an infected index patient.

DETAILS: This phase 3, double-blind, randomized, placebo-controlled trial was conducted between June 2023 and mid-September 2024 across the United States, Argentina, Japan, South Africa, and Vietnam. Eligible household contacts were 12 years of age or older, had a negative SARS-CoV-2 test at enrollment, and were randomized within 72 hours after symptom onset in the index patient. Participants received either ensitrelvir 375 mg on day 1 followed by 125 mg once daily on days 2-5 or matching placebo. The primary endpoint was laboratory-confirmed Covid-19 by day 10 in the modified intention-to-treat population, defined as RT-PCR positivity accompanied by at least one prespecified Covid-19 symptom lasting 48 hours or longer. Secondary endpoints included laboratory-confirmed SARS-CoV-2 infection regardless of symptoms, subgroup analyses, and safety outcomes. Overall, 2,387 household contacts were randomized, including 1,030 participants in the ensitrelvir group and 1,011 in the placebo group within the modified intention-to-treat population. The mean participant age was 42.4 years, 71.1% were enrolled within 48 hours after symptom onset in the index patient, and 37.0% had at least one risk factor for severe Covid-19. By day 10, laboratory-confirmed Covid-19 occurred in 2.9% of participants receiving ensitrelvir compared with 9.0% receiving placebo, corresponding to a risk ratio of 0.33 (95% CI, 0.22-0.49; P<0.001) and an approximate 67% relative risk reduction in the modified intention-to-treat population. In the intention-to-treat population, Covid-19 developed in 4.4% and 10.2% of participants, respectively (risk ratio, 0.43; 95% CI, 0.32-0.59; P<0.001). Laboratory-confirmed SARS-CoV-2 infection irrespective of symptoms was also lower with ensitrelvir (14.0% vs. 21.5%; risk ratio, 0.66; 95% CI, 0.55-0.79). Subgroup analyses demonstrated generally consistent efficacy across age groups and participants with risk factors for severe disease. Among participants with risk factors, Covid-19 developed in 2.4% of the ensitrelvir group compared with 9.9% of the placebo group. Ensitrelvir was also associated with a 34% relative reduction in household SARS-CoV-2 transmission. Adverse events occurred at similar frequencies in the ensitrelvir and placebo groups (15.1% vs. 15.5%), with serious adverse events reported in 0.2% of participants in each group. No Covid-19-related hospitalizations or deaths occurred. Transient reductions in high-density lipoprotein concentrations were observed with ensitrelvir but returned toward baseline by day 15 and were not associated with clinical events.

Source: Hayden, F. G., Shinkai, M., Clark, T. W., et al. Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts. New England Journal of Medicine. 2026; 394(19): 1905-1915. Published: June 22, 2026. DOI: 10.1056/NEJMoa2509306.

Findings from the PRESIDE Double-Blind Randomized Controlled Trial

[Posted 7/Jul/2026]

AUDIENCE: Family Medicine, Psychiatry

KEY FINDINGS: In this pragmatic double-blind randomized controlled trial conducted in Australian primary care, pharmacogenomic-informed antidepressant prescribing did not improve depressive symptoms compared with prescribing guided by national therapeutic guidelines. Clinical outcomes, medication tolerability, adherence, and quality of life were similar between groups, while cost-effectiveness analyses did not support routine implementation of pharmacogenomic testing in this setting. These findings suggest that broad pharmacogenomic-guided antidepressant prescribing in general practice does not provide additional clinical benefit over guideline-based management, although targeted evaluation in carefully selected patient populations may warrant further investigation.

BACKGROUND: Pharmacogenomic testing has been proposed as a strategy to individualize antidepressant selection by identifying CYP2D6 and CYP2C19 variants that influence drug metabolism. Although previous studies have suggested potential clinical benefits, evidence from pragmatic primary care settings remains limited. The Pharmacogenomic-Informed Antidepressant Prescribing for Moderate-to-Severe Depressive Symptoms in Australian General Practice (PRESIDE) trial evaluated whether pharmacogenomic-guided prescribing improves depression outcomes compared with guideline-based prescribing in routine general practice.

DETAILS: PRESIDE was a multicenter, double-blind, randomized controlled trial conducted in Australian general practice between May 26, 2021, and September 28, 2023. Of 5185 patients approached, 552 were randomized, and 550 participants (275 per group) were included in the intention-to-treat analysis. Participants with moderate-to-severe depressive symptoms were assigned in a 1:1 ratio to receive antidepressant prescribing recommendations based either on pharmacogenomic testing combined with Australian Therapeutic Guidelines or on Australian Therapeutic Guidelines alone. Pharmacogenomic reports incorporated CYP2D6 and CYP2C19 metabolizer phenotypes derived from saliva-based genotyping. The primary endpoint was change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to 12 weeks after the prescribing report was received. Secondary outcomes included remission, treatment response, antidepressant-related adverse effects, medication adherence, prescribing congruence, quality of life, and cost-effectiveness. A total of 479 participants (87%) completed the primary 12-week outcome assessment. Depressive symptoms improved over time in both groups. At 12 weeks, the adjusted between-group difference in PHQ-9 change was 0.90 (95% CI, 0.06-1.75; standardized mean difference 0.23 [95% CI, 0.02-0.45]; p=0.036), indicating a small but greater improvement in depressive symptoms in the guideline-based control group. No significant between-group differences were observed at 4, 8, or 26 weeks. Remission at 12 weeks occurred in 11% of participants receiving pharmacogenomic-guided prescribing compared with 18% in the control group, corresponding to an adjusted difference of -7.22% (95% CI, -13.25 to -1.19) and an odds ratio of 0.530 (95% CI, 0.311-0.903; p=0.020). Treatment response rates did not differ significantly between groups (29% vs 32%; OR 0.874; 95% CI, 0.581-1.315; p=0.518). Approximately two-thirds of participants had an actionable CYP2D6 or CYP2C19 phenotype, yet subgroup analyses demonstrated no differential treatment benefit based on genotype. Antidepressant adherence, side-effect burden, health-related quality of life, and health-care utilization were comparable between groups. Economic analyses indicated that pharmacogenomic-guided prescribing was more costly and less effective than standard guideline-based care, although differences in costs and quality-adjusted life years were not statistically significant. No grade 2-5 adverse events occurred, and only one grade 1 adverse event related to an administrative reporting error was documented.

Source: Saya, S., Chondros, P., Abela, A., et al. Pharmacogenomic-informed antidepressant prescribing for moderate-to-severe depressive symptoms in Australian general practice (PRESIDE): a double-blind, randomised controlled trial. The Lancet Primary Care. 2026; Published: June 25, 2026. DOI: 10.1016/j.lanprc.2026.100158