Histopathology of new-onset refractory status epilepticus (NORSE) in adults.

OBJECTIVE: new-onset refractory status epilepticus (NORSE) is defined as de novo refractory seizures occurring in previously healthy adults, without a clear underlying etiology. Due to refractory seizures and insufficient understanding of pathophysiology, management of these patients remains challenging and often leads to poor clinical outcomes. Various infectious and autoimmune mechanisms have been proposed but have not been validated and a large number of patients are thus labeled 'cryptogenic'. Moreover, histopathological findings have rarely been described in NORSE and are usually autopsy evaluations. In this paper, we describe the clinical correlates and histopathological findings in patients presenting with NORSE. METHODS: A case series of five patients with NORSE who underwent neurosurgical intervention and had histopathological examination during their acute clinical course. RESULTS: In all patients,status epileptics was refractory to treatment with antiseizure drugs (ASDs) and anesthetic agents. Autoimmune work-up revealed elevated titer of anti-GAD antibody in one patient but was unremarkable in others. Empiric use of immunomodulation therapy in three patients did not lead to cessation of status epilepticus (SE). Due to failure of prolonged medical management, three patients underwent palliative surgery for resection of epileptogenic tissue whereas the other two had diagnostic brain biopsy. Histopathology obtained during biopsy revealed evidence of vasculitis in one and necrotizing vasculopathy in another. The patient with anti-GAD antibodies had evidence of lymphocytic infiltration in limbic structures. The remaining two had nonspecific histopathological findings. SIGNIFICANCE: Although our findings are limited by a small number of patients, it adds to the growing premise of NORSE being related to an underlying autoimmune process. Additional studies, especially with histopathological data are needed to better understand this devastating disorder.

Differential expression of senescence tumour markers and its implications on survival outcomes of breast cancer patients.

Breast cancer is a heterogeneous disease displaying different histopathological characteristics, molecular profiling and clinical behavior. This study describes the expression patterns of senescence markers P53, DEC1 and DCR2 and assesses their significance on patient survival as a single or combined marker with P16 or P14 using breast cancer progression series. One thousand and eighty (1080) patients with primary invasive ductal carcinoma, no special type, were recruited through an 11-year retrospective study period. We constructed tissue microarrays of normal, benign hyperplasia, ductal carcinoma in situ and invasive ductal carcinoma from each patient and performed immunohistochemical staining to study the protein expression. Statistical analysis includes Pearson chi-square, Kaplan-Meier log ran test and Cox proportional hazard regression were undertaken to determine the associations and predict the survival outcomes. P53, DEC1 and DCR2 expression correlated significantly with normal, benign, premalignant and malignant tissues with (p<0.05). The expression profile of these genes increases from normal to benign to premalignant and plateaued from premalignant to malignant phenotype. There is a significant association between P53 protein expression and age, grade, staging, lymphovascular invasion, estrogen receptor, progesterone receptor and HER2 whereas DCR2 protein expression significantly correlated with tumour grade, hormone receptors status and HER2 (p<0.05 respectively). P53 overexpression correlated with increased risk of relapse (p = 0.002) specifically in patients who did not receive hormone therapy (p = 0.005) or chemotherapy (p<0.0001). The combination of P53+/P16+ is significantly correlated with poor overall and disease-free survival, whereas a combination of P53+/P14+ is associated with worse outcome in disease-free survival (p<0.05 respectively). P53 overexpression appears to be a univariate predictor of poor disease-free survival. The expression profiles of DEC1 and DCR2 do not appear to correlate with patient survival outcomes. The combination of P53 with P16, rather P53 expression alone, appears to provide more useful clinical information on patient survival outcomes in breast cancer.

Intraoperative hippocampal electrocorticography frequently captures electrographic seizures and correlates with hippocampal pathology.

OBJECTIVE: Relationship between electrographic seizures on hippocampal electrocorticography (IH-ECoG) and presence/type of hippocampal pathology remains unclear. METHODS: IH-ECoG was recorded for 10-20 min from the ventricular surface of the hippocampus following removal of the temporal neocortex in 40 consecutive patients. Correlation between intraoperative hippocampal seizures and preoperative MRI, hippocampal histopathology, and EEG from invasive monitoring was determined. RESULTS: IH-ECoG captured electrographic seizures in 15/40 patients (in 8/23 with abnormal hippocampal signal on MRI and 7/17 patients without MRI abnormality). Hippocampal neuronal loss was observed in 22/40 (Group 1), while 18/40 had no significant neuronal loss (Group 2). In Group 1, 4/22 had seizures on IH-ECoG, while 11/18 had electrographic seizures in Group 2. In 24/40 patients who underwent prolonged extraoperative intracranial EEG (IC-EEG) recording, hippocampal seizures were captured in 14. Of these, 7 also had seizures during IH-ECoG. In 10/24 IC-EEG patients without seizures, 3 had seizures on IH-ECoG. CONCLUSIONS: IH-ECoG frequently captures spontaneous electrographic seizures. These are more likely to occur in patients with pathologic processes that do not disrupt/infiltrate hippocampus compared to patients with intractable epilepsy associated with disrupted hippocampal architecture. SIGNIFICANCE: Intraoperative hippocampal seizures may result from deafferentation from the temporal neocortex and disinhibition of the perforant pathway.

Management of brain tumor-related epilepsy.

Seizures are common in both primary and metastatic brain tumors, although the rate of seizures differ significantly between the different types of neoplasms. Patients with brain tumor-associated seizures need treatment with antiepileptic drugs (AEDs) to prevent recurrence, whereas strong clinical data exists to discourage routine prophylaxis in patients who have not had seizures. The newer AEDs, such as levetiracetam, lamotrigine, lacosamide, topiramate, or pregabalin, are preferable for various reasons, primarily related to the side-effect profile and limited interactions with other drugs. If seizures persist despite initiation of an appropriate monotherapy (in up to 30-40% of cases), additional anticonvulsants may be necessary. Early surgical intervention improves seizure outcomes in individuals with medically refractory epilepsy, especially in patients with a single lesion that is epileptogenic. Data for this review article were compiled by searching for scholarly articles using the following keywords: brain tumor, epilepsy, seizure, tumor-related epilepsy, central nervous system, epidemiology, review, clinical trial, and surgery. Articles were screened for relevance by title and abstract, and selected for review and inclusion based on significant contribution to the topics discussed.

Acute Resective Surgery for the Treatment of Refractory Status Epilepticus.

BACKGROUND: To identify the role of acute surgical intervention in the treatment of refractory status epilepticus (RSE). METHODS: Retrospective review of consecutive patients who underwent epilepsy surgery from 2006 to 2015 was done to identify cases where acute surgical intervention was employed for the treatment of RSE. In addition, the adult and pediatric RSE literature was reviewed for reports of surgical treatment of RSE. RESULTS: Nine patients, aged 20-68 years, with various etiologies were identified to have undergone acute surgical resection for the treatment of RSE, aided by electrocorticography. Patients required aggressive medical therapy with antiepileptic drugs and intravenous anesthetic drugs for 10-54 days and underwent extensive neurodiagnostic testing prior to resective surgery. Eight out of nine patients survived and five patients were seizure-free at the last follow-up. The literature revealed 13 adult and 48 pediatric cases where adequate historical detail was available for review and comparison. CONCLUSIONS: We present the largest cohort of consecutive adult patients who underwent resective surgery in the setting of RSE. We also reveal that surgery can be efficacious in aborting status and in some can lead to long-term seizure freedom. Acute surgical intervention is a viable option in prolonged RSE and proper evaluation for such intervention should be conducted, although the timing and type of surgical intervention remain poorly defined.

Three- and four-dimensional mapping of speech and language in patients with epilepsy.

We have provided 3-D and 4D mapping of speech and language function based upon the results of direct cortical stimulation and event-related modulation of electrocorticography signals. Patients estimated to have right-hemispheric language dominance were excluded. Thus, 100 patients who underwent two-stage epilepsy surgery with chronic electrocorticography recording were studied. An older group consisted of 84 patients at least 10 years of age (7367 artefact-free non-epileptic electrodes), whereas a younger group included 16 children younger than age 10 (1438 electrodes). The probability of symptoms transiently induced by electrical stimulation was delineated on a 3D average surface image. The electrocorticography amplitude changes of high-gamma (70-110 Hz) and beta (15-30 Hz) activities during an auditory-naming task were animated on the average surface image in a 4D manner. Thereby, high-gamma augmentation and beta attenuation were treated as summary measures of cortical activation. Stimulation data indicated the causal relationship between (i) superior-temporal gyrus of either hemisphere and auditory hallucination; (ii) left superior-/middle-temporal gyri and receptive aphasia; (iii) widespread temporal/frontal lobe regions of the left hemisphere and expressive aphasia; and (iv) bilateral precentral/left posterior superior-frontal regions and speech arrest. On electrocorticography analysis, high-gamma augmentation involved the bilateral superior-temporal and precentral gyri immediately following question onset; at the same time, high-gamma activity was attenuated in the left orbitofrontal gyrus. High-gamma activity was augmented in the left temporal/frontal lobe regions, as well as left inferior-parietal and cingulate regions, maximally around question offset, with high-gamma augmentation in the left pars orbitalis inferior-frontal, middle-frontal, and inferior-parietal regions preceded by high-gamma attenuation in the contralateral homotopic regions. Immediately before verbal response, high-gamma augmentation involved the posterior superior-frontal and pre/postcentral regions, bilaterally. Beta-attenuation was spatially and temporally correlated with high-gamma augmentation in general but with exceptions. The younger and older groups shared similar spatial-temporal profiles of high-gamma and beta modulation; except, the younger group failed to show left-dominant activation in the rostral middle-frontal and pars orbitalis inferior-frontal regions around stimulus offset. The human brain may rapidly and alternately activate and deactivate cortical areas advantageous or obtrusive to function directed toward speech and language at a given moment. Increased left-dominant activation in the anterior frontal structures in the older age group may reflect developmental consolidation of the language system. The results of our functional mapping may be useful in predicting, across not only space but also time and patient age, sites specific to language function for presurgical evaluation of focal epilepsy.

Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials.

Patients with low-grade glioma frequently have brain tumor-related epilepsy, which is more common than in patients with high-grade glioma. Treatment for tumor-associated epilepsy usually comprises a combination of surgery, anti-epileptic drugs (AEDs), chemotherapy, and radiotherapy. Response to tumor-directed treatment is measured primarily by overall survival and progression-free survival. However, seizure frequency has been observed to respond to tumor-directed treatment with chemotherapy or radiotherapy. A review of the current literature regarding seizure assessment for low-grade glioma patients reveals a heterogeneous manner in which seizure response has been reported. There is a need for a systematic approach to seizure assessment and its influence on health-related quality-of-life outcomes in patients enrolled in low-grade glioma therapeutic trials. In view of the need to have an adjunctive metric of tumor response in these patients, a method of seizure assessment as a metric in brain tumor treatment trials is proposed.

Acute or chronic use of lacosamide does not alter its distribution between serum and cerebrospinal fluid.

OBJECTIVE: The site of action for antiepileptic drugs (AEDs) is within the brain; however, cerebrospinal fluid (CSF) concentration is highly variable. Lacosamide (LCM) is approved by the U.S. Food and Drug Administration (FDA) for treatment of partial-onset seizures in adults, and has linear pharmacokinetics in serum. Penetration across the blood-brain barrier (BBB) is unknown. This study aims to provide additional insights into the pharmacokinetics of LCM. METHODS: Thirty adults undergoing craniotomy for treatment of intractable epilepsy or brain tumor were recruited and were either taking LCM long term (group 1, n = 15), or were LCM naive, receiving LCM as prophylaxis for surgery (group 2, n = 15). All patients received one intravenous (IV) dose (15 min infusion) immediately prior to craniotomy. CSF and arterial blood were collected simultaneously following craniotomy. LCM concentrations were measured in serum and CSF. RESULTS: LCM concentration differences between groups 1 and 2 for both CSF and serum were statistically significant (p ≤ 0.0005), but there was no statistically significant difference in CSF/serum ratios (group 1 = 0.726 ± 0.231; group 2 = 0.556 ±0.241; p = 0.0585). LCM concentration in serum correlated positively with CSF concentration in group 1 (Pearson r = 0.8527, p < 0.0001). The time interval between the end of dose delivery and sample collection correlated positively with the CSF/serum ratio for the drug-naive group (Pearson r = 0.6525; p = 0.0084). Treatment with other AEDs did not affect LCM distribution between serum and CSF. SIGNIFICANCE: Although chronic dosing resulted in higher LCM concentrations in serum and CSF compared to drug-naive patients, the CSF/serum ratio was not affected by LCM pretreatment. These data suggest that LCM serum concentration may reliably predict CSF concentration.

Evaluation of magnetic resonance imaging-negative drug-resistant epilepsy.

A structural brain lesion in patients with drug-resistant epilepsy (DRE) greatly increases the likelihood of identification of the seizure focus and ultimately seizure-free outcome following resective epilepsy surgery. In contrast, surgical outcomes of true non-lesional DRE are less favorable. Therefore, discovery of an underlying lesion is paramount in the pre-surgical work-up of patients with DRE. Over the years, the surgical treatment of pharmacoresistant epilepsy has evolved from straightforward lesional cases to include cases with hippocampal sclerosis. With the advent of magnetic resonance imaging (MRI), most cases of mesial temporal sclerosis became more easily identifiable on pre-operative neuroimaging. With the widespread use of high-resolution MRI with epilepsy protocols over the last two decades, our ability to visualize subtle structural changes has been greatly enhanced. However, there are some cases of lesional epilepsy, which remain unidentified on these routine MRIs. In such "non-lesional" refractory epilepsies, further investigation with advanced neuroimaging techniques, including metabolic imaging, as well as electrophysiological studies may help to identify the previously non-visualized focal brain abnormalities. In this review, we outline the current status for evaluation of MRI-negative DRE.

Invasive electroencephalography monitoring: Indications and presurgical planning.

Electroencephalography (EEG) remains a "gold standard" for defining seizures; hence identification of epileptogenic zone for surgical treatment of epilepsy requires precise electrographic localization of the seizures. Routine scalp EEG recording is not sufficient in many instances, such as extratemporal lobe epilepsy or non-lesional temporal lobe epilepsy. In these individuals EEG recording from proximity of the seizure focus is necessary, which can be achieved by placing electrodes on the surface or in the substance of the brain. As this process requires invasive procedures (usually necessitating surgical intervention) EEG obtained via these electrodes is defined as invasive electroencephalography (iEEG). As only limited areas of the brain can be covered by these electrodes in an individual, precise targeting of the presumed seizure onset location is crucial. The presurgical planning includes where to place electrodes, which type of the electrodes to choose and planned duration of the intracranial recording. Though there are general principles that guide such endeavor, each center does it slightly differently depending upon the various technologies available to them and expertise and preferences of the epilepsy surgery team. Here we describe our approach to iEEG recording. We briefly describe the background, types of iEEG recording and rationale for each, various electrode types, and scenarios where iEEG might be useful. We also describe planning of iEEG recording once the need has been established as well as our decision making process of deciding about location of electrode placement, type of electrodes to use, length of recording, choice of arrays, mapping of eloquent cortex and finally surgical planning and decisions.

Evaluating signal-correlated noise as a control task with language-related gamma activity on electrocorticography.

OBJECTIVE: Our recent electrocorticography (ECoG) study suggested reverse speech, a widely used control task, to be a poor control for non-language-related auditory activity. We hypothesized that this may be due to retained perception as a human voice. We report a follow-up ECoG study in which we contrast forward and reverse speech with a signal-correlated noise (SCN) control task that cannot be perceived as a human voice. METHODS: Ten patients were presented 90 audible stimuli, including 30 each of corresponding forward speech, reverse speech, and SCN trials, during ECoG recording with evaluation of gamma activity between 50 and 150 Hz. RESULTS: Sites of the lateral temporal gyri activated throughout speech stimuli were generally less activated by SCN, while some temporal sites seemed to process both human and non-human sounds. Reverse speech trials were associated with activities across the temporal lobe similar to those associated with forward speech. CONCLUSIONS: Findings herein externally validate functional neuroimaging studies utilizing SCN as a control for non-language-specific auditory function. Our findings are consistent with the notion that stimuli perceived as originating from a human voice are poor controls for non-language auditory function. SIGNIFICANCE: Our findings have implications in functional neuroimaging research as well as improved clinical mapping of auditory functions.

Systems biology of human epilepsy applied to patients with brain tumors.

Epilepsy is a disease of recurrent seizures that can be associated with a wide variety of acquired and developmental brain lesions. Current medications for patients with epilepsy can suppress seizures; they do not cure or modify the underlying disease process. On the other hand, surgical removal of focal brain regions that produce seizures can be curative. This surgical procedure can be more precise with the placement of intracranial recording electrodes to identify brain regions that generate seizure activity as well as those that are critical for normal brain function. The detail that goes into these surgeries includes extensive neuroimaging, electrophysiology, and clinical data. Combined with precisely localized tissues removed, these data provide an unparalleled opportunity to learn about the interrelationships of many "systems" in the human brain not possible in just about any other human brain disorder. Herein, we describe a systems biology approach developed to study patients who undergo brain surgery for epilepsy and how we have begun to apply these methods to patients whose seizures are associated with brain tumors. A central goal of this clinical and translational research program is to improve our understanding of epilepsy and brain tumors and to improve diagnosis and treatment outcomes of both.

Histopathological evidence that hippocampal atrophy following status epilepticus is a result of neuronal necrosis.

Medial temporal lobe epilepsy is commonly associated with hippocampal atrophy on MRI and hippocampal sclerosis on histopathological examination of surgically-resected specimens. Likewise, it is well-established that prolonged seizures and status epilepticus can lead to hippocampal edema as noted on MRI. In this paper, the authors present an unusual patient with prolonged refractory status epilepticus, due to limbic encephalitis associated with anti-GAD antibody, who underwent palliative epilepsy surgery. Bilateral hippocampal edema was noted on preoperative MRI. Histologic evaluation confirmed presence of acute necrosis and neuronal loss in the left hippocampal formation. Follow-up MRI several months after surgery demonstrated severe atrophy of the contralateral right hippocampus. This is the first clear histopathological evidence that hippocampal atrophy following status epilepticus is the result of acute neuronal necrosis and cell loss.

Successful surgical treatment of an inflammatory lesion associated with new-onset refractory status epilepticus.

New-onset refractory status epilepticus (NORSE) has high morbidity and mortality. The authors describe the successful surgical treatment of a 56-year-old man presenting with NORSE. Magnetic resonance imaging showed a left temporal lobe lesion suspicious for a low-grade tumor, while PET imaging with the alpha[(11)C]methyl-L-tryptophan (AMT) radiotracer showed increased cortical uptake extending beyond this lesion and partly overlapping with epileptogenic cortex mapped by chronic intracranial electroencephalographic monitoring. Resection of the epileptic focus resulted in long-term seizure freedom, and the nonresected portion of the PET-documented abnormality normalized. Histopathology showed reactive gliosis and inflammatory markers in the AMT-PET-positive cortex. Molecular imaging of neuroinflammation can be instrumental in the management of NORSE by guiding placement of intracranial electrodes or assessing the extent and severity of inflammation for antiinflammatory interventions.

Gamma activity modulated by picture and auditory naming tasks: intracranial recording in patients with focal epilepsy.

OBJECTIVE: We measured the spatial, temporal and developmental patterns of gamma activity augmented by picture- and auditory-naming tasks and determined the clinical significance of naming-related gamma-augmentation. METHODS: We studied 56 epileptic patients (age: 4-56 years) who underwent extraoperative electrocorticography. The picture-naming task consisted of naming of a visually-presented object; the auditory-naming task consisted of answering an auditorily-presented sentence question. RESULTS: Naming-related gamma-augmentation at 50-120 Hz involved the modality-specific sensory cortices during stimulus presentation and inferior-Rolandic regions during responses. Gamma-augmentation in the bilateral occipital and inferior/medial-temporal regions was more intense in the picture-naming than auditory-naming task, whereas that in the bilateral superior-temporal, left middle-temporal, left inferior-parietal, and left frontal regions was more intense in the auditory-naming task. Patients above 10 years old, compared to those younger, showed more extensive gamma-augmentation in the left dorsolateral-premotor region. Resection of sites showing naming-related gamma-augmentation in the left hemisphere assumed to contain essential language function was associated with increased risk of post-operative language deficits requiring speech therapy (p < 0.05). CONCLUSIONS: Measurement of gamma-augmentation elicited by either naming task was useful to predict postoperative language deficits. SIGNIFICANCE: A smaller degree of frontal engagement in the picture-naming task can be explained by no requirement of syntactic processing or less working memory load. More extensive gamma-augmentation in the left dorsolateral-premotor region in older individuals may suggest more proficient processing by the mature brain.

Palinacousis--evidence to suggest a post-ictal phenomenon.

INTRODUCTION: Palinacousis is a paroxysmal auditory illusion in which perseveration of an external auditory stimulus occurs after cessation of the stimulus. The subjects recognize the illusory nature of this experience, which is often a fragment of the last sentence they heard. Palinacousis has been reported in only a few documented cases. It has been described as an aura, a component of complex partial seizures, and a post-ictal event. We put forward evidence demonstrating palinacousis as a post-ictal event. CASE: A 68-year-old woman presented with an acute sensory aphasia, and an EEG showed frequent epileptiform discharges from the left temporo-parietal region. MRI showed an enhancing mass in the left inferior parietal lobule that was consistent with a metastasis. A CT scan of the thorax later showed an enhancing mass in the left lung that was determined to be an invasive non-small cell carcinoma. Treatment with levetiracetam resulted in loss of epileptiform activity on EEG and resolution of aphasia, but soon afterward, she started complaining of recurrent auditory illusions in her right ear. These consisted of phrases from the ends of sentences she heard. Continuous EEG monitoring during her auditory symptoms showed intermittent left temporal slowing but no epileptiform discharges or electrographic seizures. An FDG-PET scan with the glucose uptake phase during episodes of auditory illusions revealed hypometabolism of bilateral medial temporal cortices and increased uptake in the metastatic tumor. REVIEW OF LITERATURE: A systematic review identified 14 cases with palinacousis since 1981. Cases prior to that were excluded due to the lack of sufficient data. DISCUSSION: We propose that palinacousis is a "negative" phenomenon, at least in some individuals. It occurs with a loss of function of a region of the brain that normally suppresses auditory perseveration.

Evaluating reverse speech as a control task with language-related gamma activity on electrocorticography.

Reverse speech has often been used as a control task in brain-mapping studies of language utilizing various non-invasive modalities. The rationale is that reverse speech is comparable to forward speech in terms of auditory characteristics, while omitting the linguistic components. Thus, it may control for non-language auditory functions. This finds some support in fMRI studies indicating that reverse speech resulted in less blood-oxygen-level-dependent (BOLD) signal intensity in perisylvian regions than forward speech. We attempted to externally validate a reverse speech control task using intracranial electrocorticography (ECoG) in eight patients with intractable focal epilepsy. We studied adolescent and adult patients who underwent extraoperative ECoG prior to resective epilepsy surgery. All patients received an auditory language task during ECoG recording. Patients were presented 115 audible question stimuli, including 30 reverse speech trials. Reverse speech trials more strongly engaged bilateral superior temporal sites than did the corresponding forward speech trials. Forward speech trials elicited larger gamma-augmentation at frontal lobe sites not attributable to sensorimotor function. Other temporal and frontal sites of significant augmentation showed no significant difference between reverse and forward speech. Thus, we failed to validate reported evidence of weaker activation of temporal neocortices during reverse compared to forward speech. Superior temporal lobe engagement may indicate increased attention to reverse speech. Reverse speech does not appear to be a suitable task for the control of non-language auditory functions on ECoG.

Refractory status epilepticus secondary to CNS vasculitis, a role for epilepsy surgery.

Central nervous system (CNS) vasculitis is a rare group of disorders that affect vessels of the brain parenchyma and meninges. It presents with headache, cognitive changes, or seizures, yet without aggressive management, it carries a high degree of morbidity and mortality. Refractory status epilepticus (SE) has been reported with CNS vasculitis. Patients are treated with immunosuppression, antiepileptic drugs (AED), and anesthetic agents. Outcomes are usually poor. Epilepsy surgery for refractory partial SE has succeeded in patients. We present a comparison of two patients with refractory partial SE due to CNS vasculitis. One patient was treated medically and died, while the other underwent epilepsy surgery to remove the epileptic focus along with medical therapy and the patient had substantial recovery. We describe clinical, electrophysiological, pathological, and treatment features of both patients and discuss rationale for surgical intervention. This is the first case report of the use of epilepsy surgery for the treatment of refractory SE associated with CNS vasculitis.

Lead breakage and vocal cord paralysis following blunt neck trauma in a patient with vagal nerve stimulator.

Patients with medically intractable seizures who are not candidates for epilepsy surgery are left with few options. Vagal nerve stimulation therapy is often a viable alternative for these patients and can have a positive impact on quality of life. Rarely complications may occur. We report a case of mild blunt neck trauma resulting in VNS malfunction and delayed vocal cord paralysis. A systematic review of the literature on VNS malfunction, self-inflicted injuries, vagal nerve injury, and common side effects including voice changes was performed. Only a handful of relevant publications were found. Symptoms following VNS dysfunction include pain, dyspnea, and dysphonia. These symptoms are usually nonspecific, and in many cases, do not help differentiate from vagal nerve traction, lead breakage, or pulse generator malfunction. In our case, lead fracture and visible traction injury to the left vagus nerve were seen during surgical exploration. The vocal cord function completely recovered after revision of the leads. Prompt medical attention including appropriate diagnostic studies and early surgical exploration is necessary in cases of delayed vocal cord dysfunction and can help prevent long-term complications such as neuroma formation. The authors present a unique case of reversible vocal cord injury from blunt neck trauma leading to left vagus nerve damage.