Faculty Bibliography

The term "startle" describes a sudden involuntary movement of the body in response to an unexpected stimulus. The startle reflex in humans is a normal physiologic symmetric flexor response present starting around 6 weeks of age and remaining for life. Conditions with an abnormal or exaggerated startle are collectively referred to as startle syndromes, and are a rare, heterogeneous group of disorders. The startle syndromes are categorized into three broad groups: (1) hyperekplexia, (2) stimulus-induced disorders, and (3) neuropsychiatric startle disorders. While startle syndromes are often relatively benign, medical emergencies can arise as complications from the abnormal startle. Most concerning is the increased morbidity and mortality from apneic episodes in patients with hyperekplexia, which can unfortunately lead to sudden death. Therefore, prompt recognition and treatment of this disorder is imperative. In this chapter, we review the normal human startle reflex and then provide an overview of the startle syndromes, with a particular focus on hyperekplexia given the movement disorder emergencies seen in this syndrome.
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Posthypoxic myoclonus (PHM) is a possible sequela of acute hypoxic events. An acute form and a chronic form (the latter also referred to as Lance-Adams syndrome, LAS) have been described. Acute PHM is usually associated with a poor prognosis. LAS, instead, is characterized by myoclonus presenting or persisting as patients regain consciousness. It can improve over time, and when additional neurological symptoms are present those are usually mild. Differentiating these two phenotypes based on clinical and neurophysiological assessments (such as electroencephalogram recordings and somatosensory evoked potentials) is not always straightforward, although very important because of the different prognostic implications. There are differences in therapeutic approaches for acute and chronic PHM because of the different nature of the myoclonus (cortical vs. subcortical or a combination of the two) and concurrent events. Multidrug approaches are usually required in both settings, mostly leveraging antiepileptic medications. In patients with persistent and debilitating LAS, multistep and even surgical approaches, such as deep brain stimulation, can be attempted to maximize functional recovery.
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Although tardive and neuroleptic-induced movement disorders are not typically viewed as neurologic emergencies, in rare instances they may manifest in ways that can produce severe bodily discomfort or even threaten vital functions like breathing and swallowing. The continued widespread use of dopamine receptor-blocking agents in the hospital and outpatient setting has necessitated their recognition, as prompt diagnosis and treatment are critical for the prevention of sometimes life-threatening complications. In this chapter, we review the history, clinical presentation, and management of neuroleptic-induced respiratory and gastrointestinal phenomena and oculogyric crisis.
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AIMS/OBJECTIVE:The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS:Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS:We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS:These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

OBJECTIVES/OBJECTIVE:To assess whether MR fingerprinting (MRF)-based relaxation properties exhibit cross-sectional and prospective correlations with patient outcome and compare the results with those from DTI. METHODS:from MRF were compared in 12 gray and white matter regions with Mann-Whitney tests. Bivariate associations between MR measures and outcome were assessed using the Spearman correlation and logistic regression. RESULTS:, accounted for five of the six MR measures with the highest utility for identification of non-recovered patients at timepoint 2 (AUC > 0.80). CONCLUSION/CONCLUSIONS:, FA, and ADC for predicting 3-month outcome after mTBI. KEY POINTS/CONCLUSIONS:, and FA.

PURPOSE/OBJECTIVE:Gait improvement following high-volume lumbar puncture (HVLP) and continuous lumbar drain (cLD) is widely used to predict shunt response in patients with suspected normal pressure hydrocephalus (NPH). Here, we investigate differences in MRI volumetric and traditional measures between HVLP/cLD responders and non-responders to identify imaging features that may help predict HVLP/cLD response. METHODS:Eighty-two patients with suspected NPH were studied retrospectively. Gait testing was performed before and immediately/24 h/72 h after HVLP/cLD. A positive response was defined as improvement in gait post-procedure. Thirty-six responders (26 men; mean age 79.3 ± 6.3) and 46 non-responders (25 men; mean age 77.2 ± 6.1) underwent pre-procedure brain MRI including a 3D T1-weighted sequence. Subcortical regional volumes were segmented using FreeSurfer. After normalizing for total intracranial volume, two-way type III ANCOVA test and chi-square test were used to characterize statistical group differences. Evans' index, callosal angle (CA), and disproportionately enlarged subarachnoid space hydrocephalus were assessed. Multivariable logistic regression models were tested using Akaike information criterion to determine which combination of metrics most accurately predicts HVLP/cLD response. RESULTS:Responders and non-responders demonstrated no differences in total ventricular and white/gray matter volumes. CA (men only) and third and fourth ventricular volumes were smaller; and hippocampal volume was larger in responders (p < 0.05). Temporal horns volume correlated with degree of improvement in gait velocity in responders (p = 0.0006). The regression model was 76.8% accurate for HVLP/cLD response. CONCLUSION/CONCLUSIONS:CA and third and fourth ventricular volumes and hippocampal volume may serve as potentially useful imaging features that may help predict spinal tap response and hence potentially shunt response.

BACKGROUND:Levetiracetam is commonly used for seizure prophylaxis in patients with intracerebral hemorrhage (ICH), traumatic brain injury (TBI), supratentorial neurosurgery, and spontaneous subarachnoid hemorrhage (SAH). However, its efficacy, optimal dosing, and the adverse events associated with levetiracetam prophylaxis remain unclear. METHODS:A systematic search of PubMed, Embase, and Cochrane central register of controlled trials (CENTRAL) database was conducted from January 1, 2000, to October 30, 2020, including articles addressing treatment with levetiracetam for seizure prophylaxis after SAH, ICH, TBI, and supratentorial neurosurgery. Non-English, pediatric (aged < 18 years), preclinical, reviews, case reports, and articles that included patients with a preexisting seizure condition or epilepsy were excluded. The coprimary meta-analyses examined first seizure events in (1) levetiracetam versus no antiseizure medication and (2) levetiracetam versus other antiseizure medications in all ICH, TBI, SAH, and supratentorial neurosurgery populations. Secondary meta-analyses evaluated the same comparator groups in individual disease populations. Risk of bias in non-randomised studies - of interventions (ROBINS-I) and risk-of-bias tool for randomized trials (RoB-2) tools were used to assess risk of bias. RESULTS: = 39%, P = 0.13 for heterogeneity). There were no significant differences in meta-analyses of patients with ICH, SAH, or TBI. Adverse events of any severity were reported in a median of 8% of patients given levetiracetam compared with 21% of patients in comparator groups. CONCLUSIONS:Based on the current moderately to seriously biased heterogeneous data, which frequently used low and possibly subtherapeutic doses of levetiracetam, our meta-analyses did not demonstrate significant reductions in seizure incidence and neither supports nor refutes the use of levetiracetam prophylaxis in TBI, SAH, or ICH. Levetiracetam may be preferred post supratentorial neurosurgery. More high-quality randomized trials of prophylactic levetiracetam are warranted.

BACKGROUND:Whether to approach distal occlusions endovascularly or not in medium-sized vessels secondary to proximal large vessel occlusion stroke remains unanswered. OBJECTIVE:To investigates the technical feasibility and safety of thrombectomy for secondary posterior circulation distal, medium vessel occlusions (DMVO). METHODS:TOPMOST (Treatment fOr Primary Medium vessel Occlusion STroke) is an international, retrospective, multicenter, observational registry of patients treated for distal cerebral artery occlusions. This study subanalysis endovascularly treated occlusions of the posterior cerebral artery in the P2 and P3 segment secondary preprocedural or periprocedural thrombus migration between January 2014 and June 2020. Technical feasibility was evaluated with the modified Thrombolysis in Cerebral Infarction (mTICI) scale. Procedural safety was assessed by the occurrence of symptomatic intracranial hemorrhage (sICH) and intervention-related serious adverse events. RESULTS:Among 71 patients with secondary posterior circulation DMVO who met the inclusion criteria, occlusions were present in 80.3% (57/71) located in the P2 segment and in 19.7% (14/71) in the P3 segment. Periprocedural migration occurred in 54.9% (39/71) and preprocedural migration in 45.1% (32/71) of cases. The first reperfusion attempt led in 38% (27/71) of all cases to mTICI 3. On multivariable logistic regression analysis, increased numbers of reperfusion attempts (adjusted odds ratio (aOR)=0.39, 95% CI 0.29 to 0.88, p=0.009) and preprocedural migration (aOR=4.70, 95% CI,1.35 to 16.35, p=0.015) were significantly associated with mTICI 3. sICH occurred in 2.8% (2/71). CONCLUSION/CONCLUSIONS:Thrombectomy for secondary posterior circulation DMVO seems to be safe and technically feasible. Even though thrombi that have migrated preprocedurally may be easier to retract, successful reperfusion can be achieved in the majority of patients with secondary DMVO of the P2 and P3 segment.

Seizure risk is 10-fold higher in Alzheimer's disease patients than the general population, yet the mechanisms underlying this susceptibility and the effects of seizures on Alzheimer's disease are poorly understood. To elucidate our proposed bidirectional relationship between Alzheimer's disease and seizures, we studied Alzheimer's disease human brain samples (n = 34) and found that patients with a history of seizures (n = 14) had increased β-amyloid and tau pathology, and upregulation of the mechanistic target of rapamycin (mTOR) pathway compared to cases without known seizure history (n = 20). To establish whether seizures could accelerate Alzheimer's disease progression, we induced chronic hyperexcitability in the 5XFAD Alzheimer's disease mouse model by kindling with the chemoconvulsant pentylenetetrazol and observed that 5XFAD mice displayed higher seizure severity compared to wild type. Furthermore, kindled seizures exacerbated later cognitive impairment, Alzheimer's disease neuropathology and mTORC1 activation. Finally, we demonstrate that administration of the mTOR inhibitor rapamycin following kindled seizures rescued enhanced remote and long-term memory deficits associated with earlier kindling and prevented the seizure-induced increases in Alzheimer's disease neuropathology. These data demonstrate an important link between chronic hyperexcitability and progressive Alzheimer's disease pathology and suggest a mechanism whereby rapamycin may serve as an adjunct therapy to attenuate Alzheimer's disease progression.