Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: a treatable neurological disorder caused by TPK1 mutations.

Thiamine pyrophosphokinase (TPK) produces thiamine pyrophosphate, a cofactor for a number of enzymes, including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase. Episodic encephalopathy type thiamine metabolism dysfunction (OMIM 614458) due to TPK1 mutations is a recently described rare disorder. The mechanism of the disease, its phenotype and treatment are not entirely clear. We present two patients with novel homozygous TPK1 mutations (Patient 1 with p.Ser160Leu and Patient 2 with p.Asp222His). Unlike the previously described phenotype, Patient 2 presented with a Leigh syndrome like non-episodic early-onset global developmental delay, thus extending the phenotypic spectrum of the disorder. We, therefore, propose that TPK deficiency may be a better name for the condition. The two cases help to further refine the neuroradiological features of TPK deficiency and show that MRI changes can be either fleeting or progressive and can affect either white or gray matter. We also show that in some cases lactic acidosis can be absent and 2-ketoglutaric aciduria may be the only biochemical marker. Furthermore, we have established the assays for TPK enzyme activity measurement and thiamine pyrophosphate quantification in frozen muscle and blood. These tests will help to diagnose or confirm the diagnosis of TPK deficiency in a clinical setting. Early thiamine supplementation prevented encephalopathic episodes and improved developmental progression of Patient 1, emphasizing the importance of early diagnosis and treatment of TPK deficiency. We present evidence suggesting that thiamine supplementation may rescue TPK enzyme activity. Lastly, in silico protein structural analysis shows that the p.Ser160Leu mutation is predicted to interfere with TPK dimerization, which may be a novel mechanism for the disease.

Outcome study of the Pipeline Vantage Embolization Device (second version) in unruptured (and ruptured) aneurysms (PEDVU(R) study).

BACKGROUND: The Pipeline Vantage Embolization Device (PEDV) is the fourth-generation pipeline flow diverter for intracranial aneurysm treatment. There are no outcome studies for the second PEDV version. We aimed to evaluate safety and efficacy outcomes. Primary and secondary objectives were to determine outcomes for unruptured and ruptured cohorts, respectively. METHODS: In this multicenter retrospective and prospective study, we analyzed outcome data from eight centers using core laboratory assessments. We determined 30-day and ≥3-month mortality and morbidity rates, and 6- and 18-month radiographic aneurysm occlusion rates for procedures performed during the period July 2021-March 2023. RESULTS: We included 121 consecutive patients with 131 aneurysms. The adequate occlusion rate for the unruptured cohort at short-term and medium-term follow up, and also for the ruptured cohort at short-term follow up, was >90%. Two aneurysms (1.5%) underwent retreatment. When mortality attributed to a palliative case in the unruptured cohort, or subarachnoid hemorrhage in the ruptured cohort, was excluded then the overall major adverse event rate in respective cohorts was 7.5% and 23.5%, with 0% mortality rates for each. When all event causes were included on an intention-to-treat basis, the major adverse event rates in respective cohorts were 8.3% and 40.9%, with 0.9% and 22.7% mortality rates. CONCLUSIONS: For unruptured aneurysm treatment, the second PEDV version appears to have a superior efficacy and similar safety profile to previous-generation PEDs. These are acceptable outcomes in this pragmatic and non-industry-sponsored study. Analysis of ruptured aneurysm outcomes is limited by cohort size. Further prospective studies, particularly for ruptured aneurysms, are needed.

Can further subdivision of the Raymond-Roy classification of intracranial aneurysms be useful in predicting recurrence and need for future retreatment following endovascular coiling?

Background: The Raymond-Roy classification has been the standard for neck recurrences following endovascular coiling with three grades. Several modified classification systems with subdivisions have been reported in literature but it is unclear whether this adds value in predicting recurrence or retreatment. Our aim is to assess if these subdivisions aid in predicting recurrence and need for retreatment. Methods: A retrospective review of all patients undergoing endovascular coiling between 2013 and 2014. Patients requiring stent assistance or other embolization devices were excluded from the study. The neck residue was graded at time of coiling on the cerebral angiogram and subsequent 6, 24, and 60 months MRA. Correlation between grade at coiling and follow-up with need for subsequent retreatment was assessed. Results: Overall, 17/200 (8.5%) cases required retreatment within 5 years of initial coiling. 4/130 (3.1%) required retreatment within 5 years with initial Grade 0 at coiling, 6/24 cases (25%) of those Grade 2a, 4/20 cases (20%) Grade 2b, 3/8 (38%) Grade 3, and none of those with Grade 1. Large aneurysms ≥11 mm had an increased risk of aneurysm recurrence and retreatment. About 9.7% of ruptured aneurysms required retreatment versus 4.4% for unruptured. About 55% of carotid ophthalmic aneurysms were retreated. Conclusion: Although the modified classification system was significantly predictive of progressive recurrence and need for retreatment, no significant difference between the subdivisions of Grade 2 was observed. Similar predictive value was seen when using the Raymond-Roy classification compared to the new modified, limiting the usefulness of the new system in clinical practice.

How precise is PreSize Neurovascular? Accuracy evaluation of flow diverter deployed-length prediction.

OBJECTIVE: The use of flow-diverting stents has been increasingly important in intracranial aneurysm treatment. However, accurate sizing and landing zone prediction remain challenging. Inaccurate sizing can lead to suboptimal deployment, device waste, and complications. This study presents stent deployment length predictions offered in medical software (PreSize Neurovascular) that provides physicians with real-time planning support, allowing them to preoperatively "test" different devices in the patient's anatomy in a safe virtual environment. This study reports the software evaluation methodology and accuracy results when applied to real-world data from a wide range of cases and sources as a necessary step in demonstrating its reliability, prior to impact assessment in prospective clinical practice. METHODS: Imaging data from 138 consecutive stent cases using the Pipeline embolization device were collected from 5 interventional radiology centers in the United Kingdom and retrospectively analyzed. Prediction accuracy was calculated as the degree of agreement between stent deployed length measured intraoperatively and simulated in the software. RESULTS: The software predicted the deployed stent length with a mean accuracy of 95.61% (95% confidence interval [CI] 94.87%-96.35%), the highest reported accuracy in clinical stent simulations to date. By discounting 4 outlier cases, in which events such as interactions with coils and severe push/pull maneuvers impacted deployed length to an extent the software was not able to simulate or predict, the mean accuracy further increases to 96.13% (95% CI 95.58%-96.69%). A wide discrepancy was observed between labeled and measured deployed stent length, in some cases by more than double, with no demonstrable correlation between device dimensions and deployment elongation. These findings illustrate the complexity of stent behavior and need for simulation-assisted sizing for optimal surgical planning. CONCLUSIONS: The software predicts the deployed stent length with excellent accuracy and could provide physicians with real-time accurate device selection support.

Periprocedural to 1-year safety and efficacy outcomes with the Pipeline Embolization Device with Shield technology for intracranial aneurysms: a prospective, post-market, multi-center study.

BACKGROUND: The first and second generations of the Pipeline Embolization Device (PED) have been widely adopted for the treatment of intracranial aneurysms (IAs) due to their high associated occlusion rates and low morbidity and mortality. The objective of this study was to evaluate the safety and effectiveness of the third- generation Pipeline Shield device (PED-Shield) for the treatment of IAs. METHODS: The SHIELD study was a prospective, single-arm, multicenter, post-market, observational study evaluating the PED-Shield device for the treatment of IAs. The primary efficacy endpoint was complete aneurysm occlusion without significant parent artery stenosis or retreatment at 1-year post-procedure and the primary safety endpoint was major stroke in the territory supplied by the treated artery or neurological death. RESULTS: Of 205 subjects who consented across 21 sites, 204 subjects with 204 target aneurysms were ultimately treated (mean age 54.8±12.81 years, 81.4% [166/204] female). Technical success (ie, deployment of the PED-Shield) was achieved in 98.0% (200/204) of subjects with a mean number of 1.1±0.34 devices per subject and a single device used in 86.8% (177/204) of subjects. The primary effectiveness endpoint was met in 71.7% (143/200) of subjects while the primary safety endpoint occurred in six (2.9%) subjects, two (1.0%) of which led to neurological death. CONCLUSIONS: The findings of the SHIELD study support the safety and effectiveness of the PED-Shield for IA treatment, evidenced by high occlusion rates and low rates of neurological complications in the study population. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02719522.

Imaging features in Hirayama disease.

PURPOSE: To evaluate the MR findings in clinically suspected cases of Hirayama disease. MATERIALS AND METHODS: The pre and post contrast neutral and flexion position cervical MR images of eight patients of clinically suspected Hirayama disease were evaluated for the following findings: localized lower cervical cord atrophy, asymmetric cord flattening, abnormal cervical curvature, loss of attachment between the posterior dural sac and subjacent lamina, anterior shifting of the posterior wall of the cervical dural canal and enhancing epidural component with flow voids. The distribution of the above features in our patient population was noted and correlated with their clinical presentation and electromyography findings. OBSERVATIONS: Although lower cervical cord atrophy was noted in all eight cases of suspected Hirayama disease, the rest of the findings were variably distributed with asymmetric cord flattening, abnormal cervical curvature, anterior shifting of the posterior wall of the cervical dural canal and enhancing epidural component seen in six out of eight (75%) cases. An additional finding of thoracic extension of the enhancing epidural component was also noted in five out of eight cases. CONCLUSION: Dynamic post contrast MRI evaluation of cervicothoracic spine is an accurate method for the diagnosis of Hirayama disease.

Remote multifocal bleeding points producing a Sylvian subpial hematoma during endovascular coiling of an acutely ruptured cerebral aneurysm.

Subpial hematoma is a rare type of intracranial hemorrhage with a poor prognosis. A new mechanism to explain subpial Sylvian hematoma formation in acute post-aneurysmal subarachnoid hemorrhage (SAH) was observed during coiling of a posterior communicating artery aneurysm. Multiple small bleeding points from pial branches of the left middle cerebral artery, which were remote from the ruptured aneurysm, were observed on conventional angiography. This bleeding led to the formation of a large expanding subpial Sylvian hematoma. Similar observations have been recently demonstrated on 4D CT angiography (4D CTA). We present a case that adds evidence to the literature in support of a new mechanism of subpial hematoma formation in the setting of acute SAH. This may advocate the early use of 4D CTA and conveys a poor prognosis, which might influence treatment decisions.

Remote multifocal bleeding points producing a Sylvian subpial hematoma during endovascular coiling of an acutely ruptured cerebral aneurysm.

Subpial hematoma is a rare type of intracranial hemorrhage with a poor prognosis. A new mechanism to explain subpial Sylvian hematoma formation in acute post-aneurysmal subarachnoid hemorrhage (SAH) was observed during coiling of a posterior communicating artery aneurysm. Multiple small bleeding points from pial branches of the left middle cerebral artery, which were remote from the ruptured aneurysm, were observed on conventional angiography. This bleeding led to the formation of a large expanding subpial Sylvian hematoma. Similar observations have been recently demonstrated on 4D CT angiography (4D CTA). We present a case that adds evidence to the literature in support of a new mechanism of subpial hematoma formation in the setting of acute SAH. This may advocate the early use of 4D CTA and conveys a poor prognosis, which might influence treatment decisions.

Imaging features in Hirayama disease.

Purpose: To evaluate the MR findings in clinically suspected cases of Hirayama disease. Materials and Methods: The pre and post contrast neutral and flexion position cervical MR images of eight patients of clinically suspected Hirayama disease were evaluated for the following findings: localized lower cervical cord atrophy, asymmetric cord flattening, abnormal cervical curvature, loss of attachment between the posterior dural sac and subjacent lamina, anterior shifting of the posterior wall of the cervical dural canal and enhancing epidural component with flow voids. The distribution of the above features in our patient population was noted and correlated with their clinical presentation and electromyography findings. Observations: Although lower cervical cord atrophy was noted in all eight cases of suspected Hirayama disease, the rest of the findings were variably distributed with asymmetric cord flattening, abnormal cervical curvature, anterior shifting of the posterior wall of the cervical dural canal and enhancing epidural component seen in six out of eight (75%) cases. An additional finding of thoracic extension of the enhancing epidural component was also noted in five out of eight cases. Conclusion: Dynamic post contrast MRI evaluation of cervicothoracic spine is an accurate method for the diagnosis of Hirayama disease.