A case of acute encephalopathy with hyperperfusion detected by arterial spin labelling: Extending spectrum of acute encephalopathy with biphasic seizures and late reduced diffusion.

BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common encephalopathy syndrome among Japanese children. We report, for the first time, a case of AESD, in which magnetic resonance imaging (MRI) showed no diffusion abnormalities, but hyperperfusion was detected by arterial spin labelling (ASL). CASE REPORT: A previously healthy Japanese 1-year and 5-month-old boy was transferred to our hospital due to a consciousness disorder after >60 min of status epilepticus on the first day of fever. Brain MRI on the first day revealed no abnormal findings. On the fourth day, focal seizures of the left upper and lower limbs were observed. Thereafter, the patient's condition progressed without seizures. Diffusion-weighted imaging (DWI) on day 6 showed no abnormal findings, including a bright tree appearance. However, ASL showed hyperperfusion in the frontoparietal lobes. MRI scans on days 19 and 39 revealed that the hyperperfusion lesions on day 6 had transitioned to hypoperfusion on ASL and displayed high signal intensity on T2-weighted and fluid-attenuated inversion recovery imaging. Cerebral atrophy was also observed. Based on the clinical course and imaging findings during the chronic phase, a diagnosis of AESD was made. CONCLUSION: ASL may be more sensitive than DWI for detecting AESD lesions and should be performed in children with suspected AESD.

Pathomechanism of infantile traumatic brain injury with a biphasic clinical course and late reduced diffusion evaluated by MR spectroscopy.

BACKGROUND: Infantile traumatic brain injury (TBI) with a biphasic clinical course and late reduced diffusion (TBIRD) has recently been reported as a distinct type of TBI in infancy. However, the pathological and prognostic factors of TBIRD remain unknown. We aimed to compare patients with and without TBIRD and evaluate the pathomechanism of TBIRD using magnetic resonance spectroscopy (MRS). METHODS: Ten Japanese patients with TBI were admitted to our hospital and underwent MRS between September 2015 and September 2022 (age range, 3-15 months; median age, 8.5 months). TBIRD was diagnosed in six patients. MRS data were compared among patients with TBIRD, patients without TBIRD, and controls. Neurological prognosis was classified into grades 1 (normal) to 3 (severe). RESULTS: In patients with TBIRD, MRS revealed an increase in the glutamine (Gln) level on days 3-29, which subsequently became close to normal. The degree of Gln elevation in the non-TBIRD group was smaller (117-158 % of controls) than that in the TBIRD group (210-337 %) within 14 days. MRS in the TBIRD group showed decreased N-acetyl aspartate (NAA) concentrations. The degree of NAA decrease was more prominent in grade 3 than in grades 1 and 2. NAA levels in the non-TBIRD group were almost normal. CONCLUSIONS: Patients with TBI and markedly elevated Gln levels on MRS may develop TBIRD. Neuro-excitotoxicity is a possible pathological mechanism of TBIRD. Decreased NAA levels may be useful for predicting the prognosis of patients with TBIRD.

Efficacy of a mitochondrial drug cocktail in preventing acute encephalopathy with biphasic seizures and late reduced diffusion.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is difficult to differentiate from prolonged febrile seizures during the acute phase. Mitochondrial dysfunction-induced energy depletion is among the key mechanisms underlying acute encephalopathy. Therefore, this study aimed to examine the efficacy of a "mitochondrial cocktail" in preventing AESD. We retrospectively studied children experiencing status epilepticus associated with fever lasting more than 30 min, focusing on those who received the mitochondrial cocktail between February 2016 and December 2020, and those who did not receive it within 24 h between February 2012 and January 2014. The mitochondrial cocktail contained vitamins B1, C, and E; biotin; coenzyme Q10; and l-carnitine. AESD occurred in 1 of 41 (2.4 %) patients in the administration group and 7 of 39 (17.9 %) patients in the non-administration group. The incidence of AESD was lower in the administration group than in the non-administration group, with a significant difference (p = 0.027). The incidence of encephalopathy, including cases classified as AESD and unclassified, was 7/41 (17.1 %) and 7/39 (17.9 %) in the administration and non-administration groups, respectively, with no significant difference. However, the number of cases with worsening pediatric cerebral performance category scores was significantly lower in the administration group compared to the non-administration group (p = 0.015). In conclusion, early administration of the mitochondrial cocktail may help prevent AESD. Some encephalopathy cases do not progress to a biphasic state or develop AESD. Thus, the mitochondrial cocktail should be administered as early as possible to prevent AESD.

International consensus definitions for infection-triggered encephalopathy syndromes.

AIM: To develop standardized diagnostic criteria for 'infection-triggered encephalopathy syndrome (ITES)' and five specific clinical syndromes of ITES. METHOD: The draft definitions were based on existing criteria, standardized, and discussed by a panel of international experts using nominal group technique over 18 months to achieve consensus. All criteria use the same format: (1) presence of infection/fever; (2) clinical features including encephalopathy; (3) neuroradiological features on magnetic resonance imaging; (4) exclusion of other causes. RESULTS: We first highlighted differences between ITES and infectious and autoimmune encephalitis, which is the most important differential diagnosis. Consensus was achieved to define five specific ITESs: acute encephalopathy with biphasic seizures and late reduced diffusion; acute necrotizing encephalopathy; mild encephalopathy with a reversible splenial lesion; acute fulminant cerebral oedema; and acute shock with encephalopathy and multiorgan failure. Two further conditions that are currently classified as epilepsy syndromes but have similar features to ITES, namely febrile infection-related epilepsy syndrome and hemiconvulsion-hemiplegia-epilepsy syndrome, are also discussed. INTERPRETATION: The consensus definition is expected to improve awareness of this disease concept, provide diagnostic framework, and facilitate future international research and clinical trials.

Chloride Voltage-Gated Channel 2 (CLCN2)-Related Leukoencephalopathy Exhibiting Reduced Choline Levels on Magnetic Resonance Spectroscopy.

In this article, we report the third case of chloride voltage-gated channel 2 (CLCN2)-related leukoencephalopathy (CC2L) in Japan. The patient presented with headache, vertigo, and mild visual impairment. The CLCN2 variant of the patient, NM_004366.6:c.61dup, p.(Leu21Profs*27), was also found in two other Japanese patients as this variant is relatively common in the Japanese population. Magnetic resonance imaging (MRI) revealed T2 prolongation with reduced diffusion in the bilateral posterior limbs of the internal capsule, cerebral peduncles, and superior and middle cerebellar peduncles. Magnetic resonance spectroscopy (MRS) of normal-appearing white matter revealed decreased choline content. This represents the first evidence of decreased choline levels in CC2L, highlighting the superior sensitivity of MRS over MRI.

Clinical characteristics of SARS-CoV-2-associated encephalopathy in children: Nationwide epidemiological study.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sometimes triggers acute encephalopathy as a serious neurological complication in children. We previously reported the clinico-radiological findings of SARS-CoV-2-associated encephalopathy. The advent of the SARS-CoV-2 omicron variant led to a marked increase in pediatric patients with coronavirus disease 2019 (COVID-19); however, epidemiological changes with acute encephalopathy according to the emergence of SARS-CoV-2 have not yet been documented. Therefore, the present study investigated epidemiological differences in SARS-CoV-2-associated encephalopathy during the BA.1/BA.2 and BA.5 predominant periods and also between SARS-CoV-2-associated and non-SARS-CoV-2-associated encephalopathy. METHODS: We conducted a nationwide survey of SARS-CoV-2-associated encephalopathy in Japanese children between June and November 2022. We compared the present results during the BA.5 predominant period and previous findings during the BA.1/BA.2 predominant period. We also compared the clinico-radiological syndromes of encephalopathy between SARS-CoV-2-associated and non-SARS-CoV-2-associated encephalopathy. RESULTS: Although many patients with SARS-CoV-2-associated encephalopathy in the BA.5 predominant period had seizures as their initial symptoms, no significant differences were observed in the clinical features. Patients with SARS-CoV-2-associated encephalopathy had worse outcomes than those with non-SARS-CoV-2-associated encephalopathy (p-value = 0.003). Among 103 patients with SARS-CoV-2-associated encephalopathy, 14 (13.6%) had severe types of acute encephalopathy, namely, encephalopathy with acute fulminant cerebral edema (AFCE) and hemorrhagic shock and encephalopathy syndrome (HSES). Also, 28 (27.2%) patients with SARS-CoV-2-associated encephalopathy had poor outcome: severe neurological sequelae or death. Ninety-five patients (92.2%) were not vaccinated against SARS-CoV-2. CONCLUSIONS: In SARS-CoV-2-associated encephalopathy, high percentages of AFCE and HSES can result in poor outcomes.

Factors influencing the development of infantile traumatic brain injury with a biphasic clinical course and late reduced diffusion.

BACKGROUND: Infantile traumatic brain injury (TBI) with a biphasic clinical course and late reduced diffusion (TBIRD) has been reported as a type of TBI. However, it remains uncertain which pediatric patients with TBI develop TBIRD. METHODS: Patients with TBI who were admitted to our hospital and underwent magnetic resonance imaging (MRI) between December 2006 and October 2022 were included in this study. A diagnosis of TBIRD was made in patients with or suspected TBI, with initial symptoms being convulsions or disturbance of consciousness and late-onset subcortical reduced diffusion, the so-called bright tree appearance. Clinical features, neuroimaging (computed tomography (CT) and MRI) findings, laboratory data, and Tada score were retrospectively compared between TBIRD and non-TBIRD patients. Neurological prognosis was assessed using the Pediatric Cerebral Performance Category scale. RESULTS: Of 21 patients who met the inclusion criteria, a diagnosis of TBIRD was made in 7 patients (median age: 8 months). The factors contributing to TBIRD development were seizures lasting over 30 min as the initial symptom (5/7 in TBIRD vs. 0/14 in non-TBIRD), tracheal intubation during initial treatment (5/7 vs. 0/14), and brain parenchymal lesions on CT (3/7 vs. 0/14), suggesting that severe TBI may progress to TBIRD. The Tada score was more positive in patients with TBIRD (6/7) than in those without (0/14). CONCLUSIONS: It is important to monitor infant patients with severe TBI for the development of TBIRD. The Tada score can be a useful tool for TBIRD prediction.

An Open-Label Administration of Bioavailable-Form Curcumin in Patients With Pelizaeus-Merzbacher Disease.

BACKGROUND: Two preclinical studies using mouse models of Pelizeaus-Merzbacher disease (PMD) have revealed the potential therapeutic effects of curcumin. In this study, we examined the effects of curcumin in patients with PMD. METHODS: We conducted a study administering an open-label oral bioavailable form of curcumin in nine patients genetically confirmed to have PMD (five to 20 years; mean 11 years) for 12 months (low doses for two months followed by high doses for 10 months). We evaluated changes in clinical symptoms as the primary end point using two scales, Gross Motor Function Measure (GMFM) and the PMD Functional Disability Score (PMD-FDS). The level of myelination by brain magnetic resonance imaging (MRI) and the electrophysiological state by auditory brainstem response (ABR) were evaluated as secondary end points. The safety and tolerability of oral curcumin were also examined. RESULTS: Increase in GMFM and PMD-FDS were noted in five and three patients, respectively, but overall, no statistically significant improvement was demonstrated. We found no clear improvement in their brain MRI or ABR. No adverse events associated with oral administration of curcumin were observed. CONCLUSIONS: Although we failed to demonstrate any significant therapeutic effects of curcumin after 12 months, its tolerability and safety were confirmed. This study does not exclude the possibility of therapeutic effects of curcumin, and a trial of longer duration should be considered to compare the natural history of the disease with the effects of curcumin.

A Brain Morphometry Study with Across-Site Harmonization Using a ComBat-Generalized Additive Model in Children and Adolescents.

Regional anatomical structures of the brain are intimately connected to functions corresponding to specific regions and the temporospatial pattern of genetic expression and their functions from the fetal period to old age. Therefore, quantitative brain morphometry has often been employed in neuroscience investigations, while controlling for the scanner effect of the scanner is a critical issue for ensuring accuracy in brain morphometric studies of rare orphan diseases due to the lack of normal reference values available for multicenter studies. This study aimed to provide across-site normal reference values of global and regional brain volumes for each sex and age group in children and adolescents. We collected magnetic resonance imaging (MRI) examinations of 846 neurotypical participants aged 6.0-17.9 years (339 male and 507 female participants) from 5 institutions comprising healthy volunteers or neurotypical patients without neurological disorders, neuropsychological disorders, or epilepsy. Regional-based analysis using the CIVET 2.1.0. pipeline provided regional brain volumes, and the measurements were across-site combined using ComBat-GAM harmonization. The normal reference values of global and regional brain volumes and lateral indices in our study could be helpful for evaluating the characteristics of the brain morphology of each individual in a clinical setting and investigating the brain morphology of ultra-rare diseases.

Neuroimaging in acute infection-triggered encephalopathy syndromes.

Acute encephalopathy associated with infectious diseases occurs frequently in Japanese children (400-700 children/year) and is the most common in infants aged 0-3 years. Acute encephalopathy is classified into several clinicoradiological syndromes; acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common subtype, followed by clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) and acute necrotizing encephalopathy (ANE). Neuroimaging, especially magnetic resonance imaging (MRI), is useful for the diagnosis, assessment of treatment efficacy, and evaluation of the pathophysiology of encephalopathy syndromes. MRI findings essential for diagnosis include delayed subcortical reduced diffusion (bright tree appearance) for AESD, reversible splenial lesions with homogeneously reduced diffusion for MERS, and symmetric hemorrhagic thalamic lesions for ANE. We reviewed several MRI techniques that have been applied in recent years, including diffusion-weighted imaging for the characterization of cerebral edema, arterial spin labeling for evaluating cerebral perfusion, and magnetic resonance spectroscopy for evaluating metabolic abnormality.

Neurochemistry evaluated by magnetic resonance spectroscopy in a patient with FBXO28-related developmental and epileptic encephalopathy.

BACKGROUND: Mutations in the FBXO28 gene, which encodes FBXO28, one of the F-box protein family, may cause developmental and epileptic encephalopathy (DEE). FBXO28-related DEE is radiologically characterized by cerebral atrophy, delayed/abnormal myelination, and brain malformation; however, no neurochemical analyses have been reported. CASE REPORT: A female Japanese infant presented with severe psychomotor delay, epileptic spasms, and visual impairment. Whole-exome sequencing revealed a de novo variant of the FBXO28 gene, leading to the diagnosis of FBXO28-related DEE. Magnetic resonance (MR) spectroscopy at 6, 12, and 32 months revealed decreased N-acetylaspartate and choline-containing compounds and increased levels of myoinositol. CONCLUSION: MR spectroscopy revealed neurochemical derangement in FBXO28-related DEE, that is, disturbed myelination secondary to neuronal damage with astrogliosis.

Prognostic factors among patients with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome: A retrospective cohort study using a nationwide inpatient database in Japan.

INTRODUCTION: Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic uremic syndrome (STEC-HUS). Understanding its prognostic factors is essential for immediate interventions. We examined early-phase unfavorable prognostic factors among patients with STEC-HUS using a nationwide database. MATERIAL AND METHODS: This is a retrospective cohort study to analyze practice patterns and identify prognostic factors among patients with STEC-HUS. We used the Diagnosis Procedure Combination Database, which includes approximately half of the acute-care hospitalized patients in Japan. We enrolled patients who were hospitalized for STEC-HUS from July 2010 to March 2020. The composite unfavorable outcome included in-hospital death, mechanical ventilation, dialysis, and rehabilitation at discharge. Unfavorable prognostic factors were assessed using a multivariable logistic regression model. RESULTS: We included 615 patients with STEC-HUS (median age, 7 years). Of them, 30 (4.9%) patients had acute encephalopathy and 24 (3.9%) died within 3 months of admission. Unfavorable composite outcome was observed in 124 (20.2%) patients. Significant unfavorable prognostic factors were age of 18 years or older, methylprednisolone pulse therapy, antiepileptic drug administration, and respiratory support within 2 days of admission. DISCUSSION: Patients requiring early steroid pulse therapy, antiepileptic drugs, and respiratory support were considered to be in poor general condition; such patients should receive aggressive intervention to avoid worse outcomes.

Severe pediatric acute encephalopathy syndromes related to SARS-CoV-2.

Background and objectives: To clarify whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection cause acute encephalopathy in children and which are the most common syndromes that cause them and what are the outcomes. Methods: A nationwide web-based survey among all members of the Japanese Society of Child Neurology to identify pediatric patients aged < 18 years who developed acute encephalopathy in Japan between 1 January 2020 and 31 May 2022 associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by polymerase chain reaction or antigen tests using pharyngeal swabs. Acute encephalopathy was defined as acute onset of impaired consciousness lasting > 24 h or an altered mental state; neurological symptoms arising within 2 weeks of onset of COVID-19 or multisystem inflammatory syndrome in children (MIS-C)/pediatric inflammatory multisystem syndrome (PIMS); evidence of SARS-CoV-2 infection; and reasonable exclusion of other diseases. Patients were divided into the known clinico-radiological acute encephalopathy syndrome group and unexplained or unclassifiable acute encephalopathy group. Outcomes were assessed by pediatric cerebral performance category (PCPC) score at hospital discharge. Results: Of the 3,802 society members, 217 representing institutions responded, and 39 patients with suspected acute encephalopathy were reported, of which 31 met inclusion criteria. Of these patients, 14 were diagnosed with known clinico-radiological acute encephalopathy syndromes, with acute encephalopathy with biphasic seizures and late reduced diffusion (five patients) being the most common. Five developed acute encephalopathy associated with MIS-C/PIMS. Among 31 patients, 9 (29.0%) had severe sequelae or died (PCPC ≥ 4). Two of three patients with encephalopathy with acute fulminant cerebral edema and two with hemorrhagic shock and encephalopathy syndrome died. The PCPC scores were higher in the known clinico-radiological acute encephalopathy syndrome group than in the unexplained or unclassifiable acute encephalopathy group (P < 0.01). Discussion: Acute encephalopathy related to SARS-CoV-2 infection was demonstrated to be more severe than that caused by other viruses in Japan. Acute encephalopathy syndromes characterized by specific neuroradiological findings was associated with poor clinical outcomes.

Multimodal MR imaging in acute exacerbation of methylmalonic acidemia.

Methylmalonic acidemia (MMA) is a disorder of methylmalonic acid metabolism caused by impaired methylmalonyl CoA mutase. Neuroimaging shows symmetric hypodensity on CT, and T2 prolongation on MRI in the globus pallidus; however, there have been only a few reports on MR spectroscopy findings and no previous reports on arterial spin labeling (ASL), both of which could reflect neurochemical derangement in MMA. We herein report an 18-month-old Sri Lankan boy presented with severe acute exacerbation of MMA due to bacteremia of Salmonella sp. O7. MRI on the seventh day showed T1 and T2 prolongation with decreased diffusion in the bilateral globus pallidus. ASL revealed hyperperfusion in the bilateral globus pallidus. MR spectroscopy showed increased choline (Cho), myo-inositol (mIns), glutamine (Gln), and lactate (Lac) in the globus pallidus; and increased Gln and Lac in the white matter. The globus pallidus is the site of high energy demand around the age of 1 year. In severe acute exacerbation of MMA, increased anaerobic metabolism due to impaired mitochondrial function may lead to hyperperfusion in the globus pallidus to compensate for a disturbed energy supply. Increased Cho, mIns, and Lac in the globus pallidus may result from active demyelination, astrogliosis, and increased anaerobic metabolism. Increased Gln in the basal ganglia and white matter may reflect excitotoxicity.

A case of early-infantile onset, rapidly progressive leukoencephalopathy with calcifications and cysts caused by biallelic SNORD118 variants.

Leukoencephalopathy with calcifications and cysts is a rare autosomal recessive genetic disorder neuroradiologically characterized by intracranial calcification, cerebral white matter disease, and multiple cysts. Although SNORD118 genes have recently been identified as a cause of this disorder, its clinical course varies for each patient. We report an early infantile case of this disease that progressed rapidly with confirmed SNORD118 variants. A 3-month-old female infant presented with epileptic seizures. Computed tomography revealed intracranial calcifications in the basal ganglia and thalamus. Magnetic resonance imaging demonstrated hyperintense lesions in the diffuse white matter on T2-weighted images starting at 7 months of age. Calcifications developed in the cerebral white matter, pons, and cerebellum. Small cysts appeared in the cerebral white matter at 1 year and 6 months. These cysts then began to increase bilaterally and expand rapidly. Although her epilepsy was controlled, she exhibited severe developmental delays and was unable to speak or walk at the age of 4 years. Whole-exome sequencing did not reveal any causal variants in the coding sequences. Further, Sanger sequencing revealed biallelic SNORD118 variants. Clinical features of this disease have not been established. To date, no cases with rapid changes in imaging results have been reported in detail prior to the appearance of cysts. Thus, we report a novel case that had an early infantile-onset and progressed rapidly with sequential appearance of calcification, white matter lesions and cysts. As SNORD118 variants might be missed by regular whole-exome sequencing, careful neuroimaging follow-up may be necessary to diagnose this disease.

Changes in the treatment of pediatric acute encephalopathy in Japan between 2015 and 2021: A national questionnaire-based survey.

BACKGROUND: Although acute encephalopathy (AE) is the most serious disorder associated with a viral infection in childhood and often causes death or neurological sequelae, standard treatments have not been established. In 2016, the Japanese Society of Child Neurology published the "Guidelines for the Diagnosis and Treatment of Acute Encephalopathy in Childhood 2016" (AE GL 2016). We conducted a questionnaire survey to evaluate the status of the treatment of pediatric AE in 2021 and the changes in treatment before and after the publication of the AE GL 2016. METHODS: In October 2021, questionnaires were mailed via the web to members of two mailing lists who were involved in the practice of pediatric neurological disorders. RESULTS: Most Japanese physicians (98 %) engaged in the treatment of pediatric AE used the AE GL 2016 as a clinical reference. From 2015 to 2021, the number of institutions that implemented targeted temperature management (TTM), vitamin administration, and continuous electroencephalographic monitoring increased significantly. Regarding the targeted temperature for TTM, the proportion of patients who were treated with normothermia (36.0-37.0 °C) increased from 2015 (55 %) to 2021 (79 %). The use of corticosteroids in patients with AE caused by a cytokine storm, which is recommended in the AE GL 2016, had already been implemented in most institutions by 2015. CONCLUSION: The AE GL 2016 could be used to disseminate the knowledge accumulated to date. Evidence of the efficacy and proper indication criteria for the treatment of AE is insufficient and must be further accumulated.

Fosphenytoin dosing regimen including optimal timing for the measurement of serum phenytoin concentration in pediatric patients.

INTRODUCTION: We aimed to evaluate the pediatric fosphenytoin dosing regimen, including optimal timing for the measurement of total serum phenytoin concentration (CPHT). METHODS: We retrospectively investigated pediatric patients with status epilepticus or seizure clusters treated with fosphenytoin between April 2013 and March 2018. Two CPHT measurements were analyzed, one 2-4 h after the loading dose and another before the second dose. Individual pharmacokinetic parameters were estimated using the Bayesian method and were used to simulate CPHT. RESULTS: The present study involved 12 pediatric patients; the loading dose of fosphenytoin was 22.1 (17.2-27.2) mg/kg. The CPHT was 13.4 (8.6-18.9) µg/mL 2-4 h after the loading dose. The CPHT estimated from individual pharmacokinetic parameters 12 and 24 h after the loading dose was 9.5 (6.7-14.2) and 5.8 (3.7-10.0) µg/mL, respectively. If fosphenytoin was administered at a loading dose of 22.5 mg/kg and a maintenance dose of 5 or 7.5 mg/kg (administered every 12 h, starting 12 h after the loading dose), then the CPHT on day 8 was estimated to be 5.74 (2.6-15.4) µg/mL at 5 mg/kg and 13.9 (5.7-31.0) µg/mL at 7.5 mg/kg. CONCLUSIONS: In pediatric patients, a maintenance dose of fosphenytoin should be started 12 h after the loading dose, and a maintenance dose of 5-7.5 mg/kg/dose every 12 h may be better than every 24 h. We recommend measuring CPHT at 2 and 12 h after the loading dose to simplify and safely adjust the dosage in clinical practice.