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What's new in neurology

What's new in neurology
Authors:
John F Dashe, MD, PhD
April F Eichler, MD, MPH
Richard P Goddeau, Jr, DO, FAHA
Janet L Wilterdink, MD
Literature review current through: Nov 2022. | This topic last updated: Dec 30, 2022.

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

CEREBROVASCULAR DISEASE

Timing of surgery after ischemic stroke (December 2022)

The risk of perioperative stroke is increased in patients with a prior ischemic stroke, though optimal timing of surgery after stroke is unclear. In a database study including nearly six million patients, the risk of postoperative ischemic stroke was increased eightfold in patients who had a stroke within 30 days before surgery, compared with those who never had a stroke [1]. The risk of recurrent stroke decreased and leveled off for surgery between 60 and 90 days after stroke, but remained elevated. The timing of surgery in patients with prior ischemic stroke should consider the risk of recurrent stroke and the risk of delaying surgery. We suggest delaying elective surgery for at least three months, and if possible up to nine months, after a stroke to reduce the risk of recurrence. (See "Perioperative stroke following noncardiac, noncarotid, and nonneurologic surgery", section on 'Timing of surgery after ischemic stroke'.)

Mechanical thrombectomy for acute stroke due to basilar artery occlusion (October 2022)

Mechanical thrombectomy (MT) is well established for treating acute ischemic stroke caused by a large artery occlusion in the anterior circulation, but the benefit for posterior circulation stroke is uncertain. The recent ATTENTION and BAOCHE randomized trials from China provide moderate-quality evidence that MT plus medical therapy, compared with medical therapy alone, is beneficial for selected patients with moderate to severe stroke caused by a basilar artery occlusion who can be treated within 24 hours of onset [2,3]. However, the results are not generalizable to all patients with basilar artery stroke, since the Chinese population has higher rates of large artery intracranial atherosclerotic disease relative to other populations. Larger randomized controlled trials in more diverse populations are needed to assess the efficacy of MT for basilar artery occlusion. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Basilar artery occlusion'.)

IVIG for vaccine-induced immune thrombotic thrombocytopenia (October 2022)

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication of adenoviral-vectored COVID-19 vaccines that presents with thrombocytopenia and thrombosis. Emerging evidence on management continues to support a role for intravenous immune globulin (IVIG) as a component of therapy, along with anticoagulation. In a new nonrandomized study involving 99 individuals with VITT presenting with cerebral venous thrombosis, receipt of IVIG was associated with lower mortality (29 versus 70 percent) [4]. In contrast, the choice of anticoagulant (heparin versus a nonheparin agent) and receipt of a platelet transfusion were not associated with statistically different mortality rates. We continue to suggest IVIG plus a nonheparin agent, especially if there is concern for possible heparin-induced thrombocytopenia (HIT; including delayed or spontaneous HIT). (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)", section on 'IVIG'.)

Delayed functional improvement after intracerebral hemorrhage (September 2022)

Functional improvement after intracerebral hemorrhage (ICH) can be slow and the temporal trajectory is often uncertain. In an analysis of individual patient data from two clinical trials in nearly 1000 patients with intracerebral or intraventricular hemorrhage, 72 percent of patients had a poor functional outcome at 30 days [5]. By one year, 46 percent had recovered further and achieved a good functional outcome, including 211 (30 percent) who were functionally independent. Acute ICH complications such as sepsis, new ischemic stroke, prolonged mechanical ventilation, hydrocephalus, and the need for a gastrostomy feeding tube were predictors of poor outcome at one year. These results support the practice of providing aggressive acute treatment of patients with ICH and sustained rehabilitation to help avoid premature withdrawal of support and improve long-term outcomes. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Functional recovery'.)

Updated diagnostic criteria for cerebral amyloid angiopathy (August 2022)

For patients presenting with acute intracerebral hemorrhage, the Boston criteria have been used to specify diagnostic certainty of cerebral amyloid angiopathy (CAA) based on specific hemorrhagic findings. However, the criteria did not address nonhemorrhagic presentations of CAA. Updated Boston criteria (version 2.0) for sporadic CAA now encompass hemorrhagic and nonhemorrhagic presentations and include expanded imaging findings (cortical microbleeds and white matter features) (table 1) [6]. In a retrospective, multicenter review of 341 patients who presented with clinical features consistent with CAA and had both magnetic resonance imaging and brain tissue available for analysis, the Boston criteria version 2.0 produced a higher diagnostic accuracy for probable CAA than the previous modified Boston criteria (85 versus 80 percent) while retaining high specificity (95 percent for both). These results support the utility of these updated criteria to identify patients with CAA. (See "Cerebral amyloid angiopathy", section on 'The Boston criteria for CAA'.)

DEMENTIA

Risk of progression to dementia in Down syndrome (October 2022)

Down syndrome (DS) is now considered a genetically determined form of Alzheimer disease (AD), with an estimated age of onset (53.8 years) and age of death (58.4 years) similar to that seen in autosomal dominant AD [7]. In one series of 632 adults with DS and varying levels of cognitive disability (436 asymptomatic, 69 with prodromal AD, and 127 with AD dementia) followed for five years, progression to AD dementia was seen in 17.1 percent of asymptomatic patients and was age dependent (0.6 percent for age <40 years, 21.1 percent for 40 to 44 years, 41.4 for 45 to 49 years, and 57.5 for ≥50 years) [8]. Patients with DS should be monitored closely for cognitive decline, particularly after age 40 years. (See "Down syndrome: Management", section on 'Alzheimer disease'.)

DEMYELINATING DISEASE

Mechanisms causing disability accrual in multiple sclerosis (October 2022)

An analysis of the large Novartis-Oxford multiple sclerosis data set evaluated the two main mechanisms leading to accrual of disability in multiple sclerosis (MS), which are relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) [9]. The study found that RAW contributed to disability progression primarily in the early stages of MS. PIRA was also present early in the course of all MS phenotypes (relapsing and progressive) and became the main driver of disability in the later stages. Early use of disease-modifying therapy (DMT) delayed disability progression by several years. These findings help to clarify the relative contributions of RAW and PIRA to disability accrual in MS and support the importance of starting DMT early in the course of MS. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Relapsing versus progressive disease'.)

EPILEPSY

Surgical evaluation for drug-resistant epilepsy (October 2022)

Surgery is the treatment of choice for patients with drug-resistant epilepsy (DRE). Recent expert consensus recommendations from the International League Against Epilepsy (ILAE) support early referral for epilepsy surgery for patients with DRE (if adherent to management) up to 70 years of age, as soon as drug resistance is ascertained and regardless of epilepsy duration, seizure type, epilepsy type, localization, or comorbidities [10]. We recommend referring patients with DRE for epilepsy surgery evaluation as early as the failure of the first antiseizure medication. (See "Evaluation and management of drug-resistant epilepsy", section on 'Epilepsy surgery'.)

MOVEMENT DISORDERS

Deferiprone does not slow progression in Parkinson disease (December 2022)

Iron content is elevated in the substantia nigra of patients with Parkinson disease (PD), and brain-permeable iron chelators prevent experimentally induced degeneration of dopamine neurons in mouse models. However, in a randomized trial of 372 patients with newly diagnosed PD, deferiprone (an iron chelator) resulted in worsened functional scores and earlier need for dopaminergic therapy compared with placebo, despite decreasing nigrostriatal iron content by imaging [11]. Further studies are needed to better understand the role of iron metabolism in PD. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease", section on 'Iron metabolism'.)

Association of premenopausal oophorectomy with parkinsonism (November 2022)

Bilateral oophorectomy in premenopausal patients is associated with increased risk of serious long-term health consequences, including all-cause mortality, cardiovascular disease, stroke, and cognitive impairment; its association with parkinsonism is less clear. In a cohort study of almost 5500 age-matched premenopausal patients, those with a history of oophorectomy compared with no oophorectomy had increased rates of examination or medical record-confirmed parkinsonism (hazard ratio [HR] 1.59) [12]. While rates of Parkinson disease were similar between groups overall, risk was elevated in those with oophorectomy prior to age 43 years (HR 5.0). Despite its limitations, this study further supports our practice to suggest ovarian conservation to premenopausal patients undergoing hysterectomy for benign indications. (See "Elective oophorectomy or ovarian conservation at the time of hysterectomy", section on 'Cognitive function and neurologic disease'.)

Angiotensin receptor blocker use and risk of Parkinson disease (September 2022)

Preclinical studies suggest that activation of the renin-angiotensin system may promote neurodegeneration in Parkinson disease (PD) via pro-oxidative and/or proinflammatory effects; there is corresponding interest in angiotensin receptor blockers (ARBs) as a neuroprotective strategy. In two large retrospective cohort studies, use of an ARB was associated with lower risk of incident PD compared with nonuse (adjusted hazard ratios 0.56 and 0.62, respectively) [13,14]. In one of the studies, the association strengthened with duration of ARB use. Clinical trials are needed to further explore these associations. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease", section on 'Protective factors'.)

No benefit of anti-synuclein monoclonal antibodies in patients with Parkinson disease (August 2022)

Anti-synuclein strategies are being investigated as potential disease-modifying therapies for Parkinson disease (PD) and related disorders, but results have been disappointing thus far. In patients with early-stage PD, trials of two different monoclonal antibodies directed at alpha-synuclein, cinpanemab and prasinezumab, each showed similar clinical and radiographic outcomes in the active treatment and placebo groups at 52 weeks [15,16]. The cinpanemab trial also reported no clear differences at 104 weeks in a blinded extension phase, which was halted due to lack of efficacy. Studies of other therapies directed against alpha-synuclein in earlier stages of development are ongoing. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease", section on 'Alpha-synuclein misfolding, aggregation, and toxicity'.)

New proposed guidelines for rapid eye movement sleep behavior disorder (July 2022)

The International Rapid Eye Movement (REM) Sleep Behavior Disorder (RBD) Study Group has proposed new guidelines for RBD that include standardized definitions, physiologic recording parameters, and scoring criteria on video polysomnography (PSG) based on published studies and expert opinion [17]. The guidelines are intended to harmonize collection and interpretation of video PSG data in patients with clinical and prodromal RBD. Further studies are needed to determine the utility of these guidelines compared with current standard criteria delineated by the American Academy of Sleep Medicine scoring manual. (See "Polysomnography in the evaluation of parasomnias and epilepsy", section on 'REM sleep behavior disorder'.)

NEUROMUSCULAR DISEASE

Sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis (October 2022)

Sodium phenylbutyrate-taurursodiol (PB-TURSO) is a combination of two orally available drugs that each reduce neuronal cell death in preclinical models of amyotrophic lateral sclerosis (ALS). In a randomized trial of 137 patients with ALS (75 percent also taking riluzole and/or edaravone) who were within 18 months of symptom onset, patients assigned to PB-TURSO showed a slower median rate of monthly functional decline than those assigned to placebo by 24-week follow-up [18]. There were nonsignificant trends toward slower decline in both vital capacity and muscle strength with treatment. In a subsequent analysis of patients who continued open-label treatment (up to 35 months), those originally randomized to PB-TURSO had a longer median time to tracheostomy (26 versus 19 months) and a longer median time to first hospitalization [19]. Based on these results, the combination product received regulatory approval in the United States and Canada [20,21]. We now suggest use of PB-TURSO for all patients with ALS, along with riluzole (prioritized as initial therapy) and edaravone. (See "Disease-modifying treatment of amyotrophic lateral sclerosis", section on 'Efficacy'.)

Transaxillary decompression for neurogenic thoracic outlet syndrome (September 2022)

Surgical decompression can improve symptoms of neurogenic thoracic outlet syndrome (nTOS) refractory to conservative management, but may not be durable. In the STOPNTOS trial, decompression in patients refractory to conservative management resulted in significantly improved DASH (Disability of the Arm, Shoulder, and Hand) scores at three months compared with continued conservative treatment, and all conservatively treated patients subsequently elected to undergo surgery [22]. Postoperatively, transient neurologic complications occurred in 7 of 46 patients, and 9 patients had persistent or recurrent nTOS after one year. These outcomes are consistent with prior observational studies and support our generally conservative approach. Additional larger trials with longer follow-up are needed to better compare surgery for refractory symptoms with ongoing conservative treatment. (See "Overview of thoracic outlet syndromes", section on 'nTOS'.)

Combination pharmacotherapy for painful diabetic neuropathy (August 2022)

Combination pharmacotherapy is frequently used for patients with painful diabetic neuropathy that does not respond to initial monotherapy, despite limited data to support the efficacy of this practice. In a multicenter trial of 130 patients with painful diabetic neuropathy who were given initial monotherapy with amitriptyline, pregabalin, or duloxetine, those whose pain did not improve at six weeks were given a second agent from a different pharmacologic class [23]. At 16-week follow-up, combination strategies consisting of pregabalin added to amitriptyline, amitriptyline added to pregabalin, or pregabalin added to duloxetine all provided greater benefit than monotherapy, and each strategy provided similar (approximately 50 percent) pain reduction relative to baseline pain. These results support the strategy of combination pharmacotherapy for patients with painful diabetic neuropathy that does not respond to initial monotherapy. (See "Management of diabetic neuropathy", section on 'Inadequate response to initial therapy'.)

Vaccine-derived poliovirus infection in Rockland County, New York (August 2022)

In June 2022, poliovirus was confirmed in an unvaccinated, immunocompetent adult resident of Rockland County, New York hospitalized with acute flaccid lower limb weakness [24]. Vaccine-derived poliovirus type 2 was detected in the patient's stool and was also identified from wastewater samples in two neighboring New York counties, reflecting community transmission. The patient had not traveled internationally during the presumed exposure period; therefore, these findings suggest transmission within the United States from a person who received a type 2-containing oral polio vaccine abroad. Unvaccinated individuals remain at risk for paralytic poliomyelitis if they are exposed to either wild or vaccine-derived poliovirus; all individuals should stay up to date on recommended poliovirus vaccination. (See "Poliomyelitis and post-polio syndrome", section on 'Epidemiology'.)

Thrombotic microangiopathy after gene therapy for spinal muscular atrophy (August 2022)

Spinal muscular atrophy is a rare genetic disorder characterized by progressive muscle weakness and atrophy; treatment is mainly supportive. Onasemnogene abeparvovec is an approved gene therapy that has demonstrated promising results in infants <2 years of age. Several recent reports have described thrombotic microangiopathy, with severe thrombocytopenia and microangiopathic hemolysis, following administration of this therapy. One case was fatal [25]. Further study is needed to determine the mechanisms, risk factors, and optimal treatment of this complication. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Gene therapy (mechanism unclear)'.)

NEUROONCOLOGY

Role of pneumocystis pneumonia prophylaxis with temozolomide (December 2022)

Patients with glioblastoma treated with daily temozolomide can develop pneumocystis pneumonia as a result of selective lymphopenia, but rates are not well characterized and use of antimicrobial prophylaxis in the neuro-oncology community is variable.

In a population-based study that included more than 5000 Canadian patients with gliomas treated with temozolomide chemoradiotherapy, the incidence of pneumocystis pneumonia within one year of treatment was low (0.74 percent) and there were few infection-related deaths [26].

In a related case-control study, the absolute risk reduction associated with prophylaxis was low (estimated number needed to treat to prevent one infection = 288), while the risk of grade 3/4 neutropenia was elevated (number needed to harm = 34) [27].

We suggest pneumocystis prophylaxis during chemoradiation in patients with glioblastoma who have additional risk factors for opportunistic infection (eg, glucocorticoid use, lymphopenia); in others, risks of prophylaxis may outweigh benefits. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Pneumocystis prophylaxis'.)

Guideline on circumscribed astrocytic gliomas, glioneuronal, and neuronal tumors (October 2022)

A new multinational guideline is available on the diagnosis and treatment of rare glial and neuronal tumors in children and adults [28]. Over 20 tumors are included in the guideline, corresponding to the 2021 update of the World Health Organization classification of central nervous system tumors. Surgery is the cornerstone of management for nearly all of these tumors, and radiation therapy is used selectively in the adjuvant and recurrent/refractory setting. Relevant molecular markers and targeted therapies are also reviewed. (See "Uncommon brain tumors", section on 'Circumscribed astrocytic gliomas'.)

Proton craniospinal irradiation in patients with solid tumor leptomeningeal disease (October 2022)

For patients with leptomeningeal disease (LMD) from solid tumors, craniospinal irradiation (CSI) with photons is typically not appropriate due to high risk of toxicity and low likelihood of meaningful benefit. However, proton CSI has an improved toxicity profile compared with photon CSI, and there has been renewed interest in its role. In a randomized phase II trial of proton CSI versus involved field radiation in 63 patients with LMD from either breast cancer or non-small cell lung cancer, proton CSI improved both median central nervous system progression-free survival (7.5 versus 2.3 months) and overall survival (9.9 versus 7.5 months) compared with involved field radiation, with no difference in the rate of serious adverse effects [29]. Although more data are needed, where available, proton CSI is an option in selected patients with LMD who have adequate functional status and controlled systemic disease. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Proton craniospinal radiation'.)

Updated prognostic tool for patients with lung cancer brain metastases (September 2022)

The diagnosis-specific graded prognostic assessment (GPA) provides survival estimates for patients with newly diagnosed brain metastases based on analysis of thousands of patients in a multicenter database. In an updated study of patients with brain metastases from lung cancer, programmed cell death ligand 1 (PD-L1) positivity (in the primary lung tumor) was identified as an additional factor associated with improved survival in patients with non-small cell lung cancer (NSCLC) adenocarcinoma [30]. With PD-L1 status included as a variable, median survival estimates for GPA groups 1 to 4 were 6, 15, 30, and 52 months, respectively (17 months overall). A revised NSCLC non-adenocarcinoma GPA and a new small cell lung cancer GPA were also provided. Updated calculators are publicly available online. (See "Overview of the treatment of brain metastases", section on 'Prognostic assessment'.)

Long-term follow-up of grade 3 oligodendroglial brain tumor trials (August 2022)

Final, long-term results from two cooperative group randomized phase III trials of radiation therapy (RT) with or without PCV (procarbazine, lomustine, and vincristine) chemotherapy in patients with grade 3 oligodendroglial tumors initiated in the 1990s have been published [31]. With a median follow-up of 18 to 19 years, 37 percent of patients with isocitrate dehydrogenase (IDH)-mutant, 1p19q-codeleted grade 3 tumors in each trial were predicted to be alive at 20 years after initial combined RT plus PCV, compared with approximately 15 percent in the RT alone groups. A nonsignificant trend towards benefit of PCV was observed in patients with IDH-mutant, noncodeleted tumors. These trials provide strong, complementary evidence supporting RT plus chemotherapy as the standard of care in patients with grade 3 oligodendrogliomas after maximal safe resection. (See "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults", section on 'Rationale for RT plus chemotherapy'.)

Integrated molecular grading proposal for meningiomas (July 2022)

A growing number of genetic alterations have been identified in meningiomas that are associated with more aggressive biology and worse outcomes, including homozygous deletion of cyclin-dependent kinase 2A (CDKN2A) and telomerase reverse transcriptase (TERT) gene alterations. A three-tiered integrated grading scheme (Integrated Grades 1, 2, and 3) based on mitotic count, chromosomal copy-number data, and CDKN2A deletion status has been proposed, which more accurately predicts risk of recurrence than the World Health Organization grading system [32]. Further validation is necessary, however, before this scheme can be used to guide treatment decisions. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Molecular risk stratification'.)

Tissue-agnostic approval for dabrafenib plus trametinib in BRAF V600E-mutated tumors (June 2022)

Combined therapy with the BRAF and MEK inhibitors dabrafenib and trametinib has been granted a tissue-agnostic accelerated approval by the US Food and Drug Administration for the treatment of patients ≥6 years of age with unresectable or metastatic solid tumors harboring mutations in BRAF V600E following progression on previous treatment and with no satisfactory alternative treatment options [33]. Approval was based on data from the open-label phase II ROAR and NCI-MATCH trials that demonstrated objective response rates in a variety of refractory solid tumors with data from the open-label phase II ROAR and NCI-MATCH trials that demonstrated objective response rates in a variety of refractory solid tumors with V600E mutations, which were highest (up to 50 percent) in gliomas and biliary tract, gynecologic, and gastrointestinal (but not colorectal) tumors [34,35]. The most common adverse events in the NCI MATCH trial were fatigue, nausea, and fever and chills. (See "Systemic therapy for advanced cholangiocarcinoma", section on 'BRAF V600E-mutated cancers'.)

PEDIATRIC NEUROLOGY

Gene therapy for early childhood cerebral adrenoleukodystrophy (November 2022)

Standard treatment for the early childhood cerebral form of adrenoleukodystrophy (ALD), caused by pathogenic variants in the ABCD1 gene, is allogenic hematopoietic cell transplantation (HCT), if the child has a human leukocyte antigen (HLA)-matched donor. Recently, the US Food and Drug Administration (FDA) approved elivaldogene autotemcel, a novel ex vivo lentiviral gene therapy consisting of autologous HCT using stem cells transfected with manufactured ABCD1 complementary DNA [36]. The approval was based upon published and unpublished data showing that survival at nine months following treatment appeared to be better in patients treated with either HLA-matched allogenic HCT or elivaldogene autotemcel compared with HLA-mismatched allogenic HCT [37]. No patient treated with elivaldogene autotemcel developed graft-versus-host disease, which can complicate allogenic HCT. These results suggest that elivaldogene autotemcel may have comparable efficacy for early cerebral ALD compared with allogeneic HCT and may be safer, particularly when compared with HLA-mismatched allogenic HCT. However, given the relatively short follow-up, the results should be regarded as preliminary. The FDA label carries a boxed warning about the risk of hematologic malignancy and life-threatening myelodysplastic syndrome. (See "X-linked adrenoleukodystrophy and adrenomyeloneuropathy", section on 'Autologous HCT with ex vivo gene therapy'.)

OTHER NEUROLOGY

CDC updates opioid prescribing guidelines (November 2022)

The United States Centers for Disease Control and Prevention (CDC) has published a new guideline for prescribing opioids for acute, subacute, and chronic pain, updating their 2016 guideline (table 2). The guideline is intended for clinicians who prescribe opioids to outpatients ≥18 years of age and does not apply to pain related to sickle cell disease, cancer, palliative care, or end of life care [38]. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Opioid therapy in the context of the opioid epidemic'.)

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