Regarding investigation of prognostic factors for HHV 6/7- associated acute encephalopathy

Even though language is essential in human communication, research on pharmacological therapies for language deficits in highly prevalent neurodegenerative and vascular brain diseases has received little attention. Emerging scientific evidence suggests that disruption of the cholinergic system may play an essential role in language deficits associated with Alzheimer’s disease and vascular cognitive impairment, including post-stroke aphasia. Therefore, current models of cognitive processing are beginning to appraise the implications of the brain modulator acetylcholine in human language functions. Future work should be directed further to analyze the interplay between the cholinergic system and language, focusing on identifying brain regions receiving cholinergic innervation susceptible to modulation with pharmacotherapy to improve affected language domains. The evaluation of language deficits in pharmacological cholinergic trials for Alzheimer’s disease and vascular cognitive impairment has thus far been limited to coarse-grained methods. More precise, fine-grained language testing is needed to refine patient selection for pharmacotherapy to detect subtle deficits in the initial phases of cognitive decline. Additionally, noninvasive biomarkers can help identify cholinergic depletion. However, despite the investigation of cholinergic treatment for language deficits in Alzheimer’s disease and vascular cognitive impairment, data on its effectiveness are insufficient and controversial. In the case of post-stroke aphasia, cholinergic agents are showing promise, particularly when combined with speech-language therapy to promote trained-dependent neural plasticity. Future research should explore the potential benefits of cholinergic pharmacotherapy in language deficits and investigate optimal strategies for combining these agents with other therapeutic approaches. 

/pdf/turning-the-spotlight-to-cholinergic-pharmacotherapy-of-the-5oix9t6d.pdf

Turning the Spotlight to Cholinergic Pharmacotherapy of the Human Language System.

Reply to the letter “Regarding investigation of prognostic factors for HHV 6/7-associated acute encephalopathy”

OBJECTIVE
To determine the prevalence of neuroimaging abnormalities in individuals with Down syndrome regression disorder (DSRD) and evaluate if neuroimaging abnormalities were predictive of therapeutic responses.


METHODS
A multicenter, retrospective, case-control study which reviewed neuroimaging studies of individuals with DSRD and compared them to a control cohort of individuals with Down syndrome (DS) alone was performed. Individuals aged 10-30 years and meeting international consensus criteria for DSRD were included. The presence of T1, T2/FLAIR, and SWI signal abnormalities was reviewed. Response rates to various therapies, including immunotherapy, were evaluated in the presence of neuroimaging abnormalities.


RESULTS
In total, 74 individuals (35%) had either T2/FLAIR and/or SWI signal abnormality compared to 14 individuals (12%) without DSRD (p < 0.001, 95%CI: 2.18-7.63). T2/FLAIR signal abnormalities were not appreciated more frequently in individuals with DSRD (14%, 30/210) than in the control cohort (9%, 11/119) (p = 0.18, OR: 1.63, 95%CI: 0.79-3.40). SWI signal abnormalities were appreciated at a higher frequency in individuals with DSRD (24%, 51/210) compared to the control cohort (4%, 5/119) (p < 0.001, OR: 7.31, 95%CI: 2.83-18.90). T2/FLAIR signal abnormalities were localized to the frontal (40%, 12/30) and parietal lobes (37%, 11/30). SWI signal abnormalities were predominantly in the bilateral basal ganglia (94%, 49/52). Individuals with DSRD and the presence of T2/FLAIR and/or SWI signal abnormalities were much more likely to respond to immunotherapy (p < 0.001, OR: 8.42. 95%CI: 3.78-18.76) and less likely to respond to benzodiazepines (p = 0.01, OR: 0.45, 95%CI: 0.25-0.83), antipsychotics (p < 0.001, OR: 0.28, 95%CI: 0.11-0.55), or electroconvulsive therapy (p < 0.001, OR: 0.12; 95%CI: 0.02-0.78) compared to individuals without these neuroimaging abnormalities.


INTERPRETATION
This study indicates that in individuals diagnosed with DSRD, T2/FLAIR, and SWI signal abnormalities are more common than previously thought and predict response to immunotherapy.

Neuroimaging abnormalities associated with immunotherapy responsiveness in Down syndrome regression disorder.

Trisomy 21 (T21) is a genetically determined human condition that occurs in one in every 800 births worldwide. Improvements in lifelong care have generated discussion about the mental health of people with T21. However, suicidal behavior in this population has still received little attention. This integrative review aimed to understand and synthesize scientific production on the topic of 'suicide in people with T21'. We conducted the review in the Virtual Health Library, PubMed, and PsycInfo databases using the descriptors 'Down syndrome', 'Down's syndrome', and 'trisomy 21' in combination with 'suicide', 'suicide attempted', and 'suicidal ideation'. We analyzed articles published until 10th October 2023. The selected articles were evaluated for their level of evidence and categorized thematically. Eight articles from three countries met the eligibility criteria: three case reports, three narrative literature reviews, one observational cross-sectional study, and one cohort study. The articles were organized and discussed in four categories: (1) scientific literature impressions about suicide in individuals with T21; (2) T21 life course issues and forms of expression of suicidal behavior; (3) suicide frequency in individuals with T21; and (4) possible implications for caring for individuals with T21 who exhibit suicidal behavior. The results revealed a lack of literature on the subject, which indicates the need for additional research. Based on the evidence available, suicidal behavior among people with T21, while a possible phenomenon, seems uncommon. Health professionals should investigate T21 individuals' mental health, searching for depression and self-injury symptoms. 

Suicidal behavior among individuals with trisomy 21: an integrative review

During her first year of junior high school, a 12-year-old Japanese girl with Down syndrome experienced dizziness, gait disruption, paroxysmal weakness in her hands, and sluggish speaking. Regular blood tests and a brain MRI revealed no abnormalities, and she was tentatively diagnosed with adjustment disorder. Nine months later, the patient experienced a subacute sickness of chest pain, nausea, sleep problem with night terrors, and delusion of observation. Rapid deterioration then developed with simultaneous fever, akinetic mutism, loss of facial expression, and urine incontinence. These catatonic symptoms improved after a few weeks after admission and treatment with lorazepam, escitalopram, and aripiprazole. After discharge, nonetheless, daytime slumber, empty eyes, paradoxical laughter, and declined verbal communication persisted. Upon confirmation of the cerebrospinal N-methyl-D-aspartate (NMDA) receptor autoantibody, methylprednisolone pulse therapy was tried, but it had little effect. Visual hallucinations and cenesthopathy, as well as suicidal thoughts and delusions of death, have predominated in the following years. Cerebrospinal IL-1ra, IL-5, IL-15, CCL5, G-CSF, PDGFbb, and VFGF were raised in the early stage of initial medical attention with nonspecific complaints, but were less prominent in the later stages of catatonic mutism and psychotic symptoms. We suggest a disease concept of progression from Down syndrome disintegrative disorder to NMDA receptor encephalitis, based on this experience.

/pdf/case-report-evolution-of-catatonic-mutism-and-psychotic-w0bwbw5h.pdf

Case report: Evolution of catatonic mutism and psychotic symptoms in an adolescent with Down syndrome: transition from Down syndrome disintegrative disorder to anti-N-methyl-D-aspartate receptor encephalitis

To identify prognostic factors for severe neurological sequelae and epileptic seizures in children with human herpes virus (HHV) 6/7-associated acute encephalopathy (AE).We retrospectively studied pediatric cases of HHV6/7-associated AE between April 2011 and March 2021. Neurological sequelae were assessed using the Pediatric Cerebral Performance Category scale (PCPC) and the presence of epileptic seizures 1 year after onset. We investigated the prognostic factors between the non-severe sequelae group (PCPC scores ≤ 2) and severe sequelae group (PCPC scores ≥ 3) in patients without severe neurological complications before onset.Forty patients, ranging from 4 to 95 months old, were included. AE with biphasic seizures and late reduced diffusion were the most common types of encephalopathy (n = 28). Among the 36 patients evaluated neurological sequelae, 17, nine, eight, and two were categorized as PCPC 1, 2, 3 and 4, respectively. Epileptic seizures were observed in nine patients. In the severe sequelae group, significantly more cases with coma in the acute phase and thalamic lesions on MRI and higher serum aspartate aminotransferase, alanine aminotransferase (ALT), and lactate dehydrogenase levels were observed. Multivariate analysis showed a significant between-group difference in the rate of coma (p = 0.0405). Patients with epileptic seizures had a higher rate of coma and thalamic lesions and higher serum ALT and urinary beta 2-microglobulin levels, but there was no significant difference in the multivariate analysis.In HHV6/7-associated AE, coma was a significant prognostic factor for severe neurological sequelae. 

Neurological prognostic factors for human herpes virus 6/7-associated acute encephalopathy in children: A single-center study

Acyclovir (ACV), an antiviral drug commonly used in children, is associated with neuro- and nephron-toxicity. However, ACV neurotoxicity is mainly reported in adults and rare in children. Herein, we report the case of a boy with impaired consciousness following ACV treatment, posing challenges in differentiating posterior reversible encephalopathy syndrome (PRES) from ACV neurotoxicity. Additionally, we reviewed existing literature on ACV neurotoxicity. A healthy 10-year-old boy developed severe headache and intermittent restlessness and was diagnosed with mild encephalitis/encephalopathy showing a reversible splenial lesion on magnetic resonance imaging (MRI). Since herpes simplex encephalitis could not be ruled out, ACV was initially administered. The patient later developed renal dysfunction, hypertension, and conscious disturbance. With a high serum ACV level of 14.3 μg/mL (reference; 0.4–2.0 μg/mL), we suspected PRES or ACV neurotoxicity. Upon discontinuation of ACV and starting antihypertensive therapy, the patient's consciousness improved, leading to discharge without sequelae. In 14 pediatric cases with ACV neurotoxicity, including our case, the median age at onset was 10 years (range, 0–17 years), with renal dysfunction and high doses of ACV posing risk similar to adult cases. The mean time from ACV discontinuation to complete recovery was 5.6 ± 3.6 days, and the patients' prognosis was good. When a patient develops neurological symptoms during ACV treatment, considering the simultaneous occurrence of ACV neurotoxicity and PRES is crucial, including measuring their blood pressure, renal function, ACV levels, and MRI. Additionally, dosage should be adjusted based on ACV concentration in blood. 

Differential diagnosis of posterior reversible encephalopathy syndrome and acyclovir neurotoxicity in children: A literature review of acyclovir neurotoxicity

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Case report: Evolution of catatonic mutism and psychotic symptoms in an adolescent with Down syndrome: transition from Down syndrome disintegrative disorder to anti-N-methyl-D-aspartate receptor encephalitis

Neurological prognostic factors for human herpes virus 6/7-associated acute encephalopathy in children: A single-center study

Reply to the letter “Regarding investigation of prognostic factors for HHV 6/7-associated acute encephalopathy”

Differential diagnosis of posterior reversible encephalopathy syndrome and acyclovir neurotoxicity in children: A literature review of acyclovir neurotoxicity