Diagnostic Challenges of Lyme Neuroborreliosis in Inpatient Neurology: A Case Series.

Lyme disease is a multisystem disorder transmitted through the Ixodes tick and is most commonly diagnosed in northeastern and mid-Atlantic states, Wisconsin, and Minnesota, though its disease borders are expanding in the setting of climate change. Approximately 10%-15% of untreated Lyme disease cases will develop neurologic manifestations of Lyme neuroborreliosis (LNB). Due to varying presentations, LNB presents diagnostic challenges and is associated with a delay to treatment. We discuss three cases of LNB admitted to our referral center in a traditionally low-incidence state to highlight clinical pearls in LNB diagnosis. Three patients from low-incidence areas with prior diagnostic evaluations presented in August with neurologic manifestations of radiculoneuritis, cranial neuropathies, and/or lymphocytic meningitis. MRI findings included cranial nerve, nerve root, and leptomeningeal enhancement leading to broad differential diagnoses. Lumbar puncture demonstrated lymphocytic pleocytosis (range 85-753 cells/uL) and elevated protein (87-318 mg/dL). Each patient tested positive for Lyme on two-tiered serum testing and was diagnosed with LNB. All three cases were associated with a delay to health care presentation (mean 20 days) and a delay to diagnosis and treatment (mean 54 days) due to under-recognition and ongoing evaluation. With the geographic expansion of Lyme disease, increasing awareness of LNB manifestations and acquiring detailed travel histories in low-incidence areas is crucial to prompt delivery of care. Clinicians should be aware of two-tiered serum diagnostic requirements and use adjunctive studies such as lumbar puncture and MRI to eliminate other diagnoses. Treatment with an appropriate course of antibiotics leads to robust improvement in neurological symptoms.

A Survey-Based Study Examining Differences in Perception of Postural Orthostatic Tachycardia Syndrome Between Patients and Primary Care Physicians.

Introduction Postural orthostatic tachycardia syndrome (POTS) is an underdiagnosed and undertreated dysautonomia. We hypothesize that there are differences between primary care physicians (PCPs) and patients' perceptions of POTS and that correcting these discrepancies may improve patient care.  Methods Two groups were surveyed: Patients who received care for POTS symptoms from a Cleveland Clinic neurologist or nurse practitioner and patients who received care from Cleveland Clinic family medicine or internal medicine physicians.  Results PCPs (81%) rated lightheadedness as the symptom with the most significant negative impact on patient's quality of life with POTS, while patients rated fatigue (32%) as their worst symptom. PCPs were somewhat comfortable managing POTS but were less confident recommending cardiac rehabilitation and daily behavioral measures.  Conclusion PCPs may need to continue review the negative impact of fatigue on the quality of life of POTS patients as well symptoms of body pain and lightheadedness. Although they are relatively comfortable managing POTS, PCPs may benefit from training on several aspects of POTS treatment.

A Structured Peer Assessment Method with Regular Reinforcement Promotes Longitudinal Self-Perceived Development of Medical Students' Feedback Skills.

BACKGROUND: Given that training is integral to providing constructive peer feedback, we examined the impact of a regularly reinforced, structured peer assessment method on student-reported feedback abilities throughout a two-year preclinical Communication Skills course. METHODS: Three consecutive 32-student medical school classes were introduced to the Observation-Reaction-Feedback method for providing verbal assessment during Year 1 Communication Skills orientation. In biweekly small-group sessions, students received worksheets reiterating the method and practiced giving verbal feedback to peers. Periodic questionnaires evaluated student perceptions of feedback delivery and the Observation-Reaction-Feedback method. RESULTS: Biweekly reinforcement of the Observation-Reaction-Feedback method encouraged its uptake, which correlated with reports of more constructive, specific feedback. Compared to non-users, students who used the method noted greater improvement in comfort with assessing peers in Year 1 and continued growth of feedback abilities in Year 2. Comfort with providing modifying feedback and verbal feedback increased over the two-year course, while comfort with providing reinforcing feedback and written feedback remained similarly high. Concurrently, student preference for feedback anonymity decreased. CONCLUSIONS: Regular reinforcement of a peer assessment framework can increase student usage of the method, which promotes the expansion of self-reported peer feedback skills over time. These findings support investigation of analogous strategies in other medical education settings. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-021-01242-w.

Cerebellar Neuromodulation for Stroke.

PURPOSE OF REVIEW: This paper reviews the current preclinical and clinical evidence for cerebellar deep brain stimulation for stroke rehabilitation. RECENT FINDINGS: We have demonstrated the effectiveness of cerebellar stimulation for stroke rehabilitation in rodent models, which has been reproduced by other groups. Synaptogenesis, neurogenesis, and vicariation of function in the perilesional cortex likely contribute to the mechanistic underpinnings of the effectiveness of this therapy. A Phase I clinical trial investigating dentate nucleus stimulation for improvement of hemiparesis due to stroke is currently underway, and results thus far are encouraging. SUMMARY: Activation of the rodent cerebellar dentate nucleus promotes functional motor recovery following stroke. Although results of a Phase I clinical trial are pending, substantial preclinical evidence indicates that deep brain stimulation of the dentate nucleus is a promising therapeutic modality.

Methods and utility of quantitative brainstem measurements in progressive supranuclear palsy versus Parkinson's disease in a routine clinical setting.

BACKGROUND AND PURPOSE: The clinical diagnosis of progressive supranuclear palsy can be challenging, as the clinical presentation overlaps with that of Parkinson's disease and multiple system atrophy. We sought to examine the practical utility of radiologic markers of progressive supranuclear palsy by investigating whether these markers could distinguish between patients with progressive supranuclear palsy-Richardson syndrome (PSP-RS) and those with Parkinson's disease based on imaging obtained in a typical clinical setting, not in a prospective research environment. MATERIALS AND METHODS: This retrospective study included 13 patients with PSP-RS and 13 patients with Parkinson's disease who were followed for either condition at our institution at the time of the study and who had MRI records available. Patients were selected without regard to type of imaging obtained. All diagnoses were confirmed by a trained movement disorders specialist using validated diagnostic criteria. Groups were matched for age and disease duration at the time of scanning. MRI records were retrospectively obtained, and image analysis was performed by investigators blinded to disease classification. Midbrain area, midbrain to pons area ratio, midbrain anterior-posterior diameter, and MR parkinsonism index were calculated for each patient. RESULTS: All established measures of identifying progressive supranuclear palsy (midbrain area, midbrain to pons area ratio, midbrain anterior-posterior diameter, and MR parkinsonism index) were significantly different between patients with PSP-RS and those with Parkinson's disease. CONCLUSION: Previously established radiographic markers distinguishing between PSP-RS and Parkinson's disease have practical utility in the clinical setting and not just in well-designed prospective analyses.

Consensus Paper: Experimental Neurostimulation of the Cerebellum.

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.

BrdU-induced hyperlocomotion in the stroked rat.

5-bromo-2'-dexoyuridine (BrdU) is often used in neuroscience research as a marker of newly-divided cells. However, several studies suggest that BrdU can produce unwanted side effects, including changes in animal behavior and cellular function. In this study, we investigated the effect of BrdU injections on locomotor behavior in a rodent model of ischemic stroke. Ischemic strokes were induced in adult rats, and 50 mg/kg BrdU was intraperitoneally injected over 5 days beginning 2 weeks post-stroke, while control animals received vehicle. Locomotor activity was evaluated by videotaping the rats in their home cages for 30 min, beginning one hour after BrdU injection. BrdU-injected rats showed a nearly three-fold increase in locomotor activity compared to control animals. These findings suggest that BrdU induces a hyperlocomotor effect in rats following brain injury, pointing to the need for caution when interpreting behavioral results in such studies.

Lateral Cerebellar Nucleus Stimulation has Selective Effects on Glutamatergic and GABAergic Perilesional Neurogenesis After Cortical Ischemia in the Rodent Model.

BACKGROUND: Chronic deep brain stimulation of the rodent lateral cerebellar nucleus (LCN) has been demonstrated to enhance motor recovery following cortical ischemia. This effect is concurrent with synaptogenesis and expression of long-term potentiation markers in the perilesional cerebral cortex. OBJECTIVE: To further investigate the cellular changes associated with chronic LCN stimulation in the ischemic rodent by examining neurogenesis along the cerebellothalamocortical pathway. METHODS: Rats were trained on the pasta matrix task, followed by induction of cortical ischemia and electrode implantation in the contralesional LCN. Electrical stimulation was initiated 6 wk after stroke induction and continued for 4 wk prior to sacrifice. Neurogenesis was examined using immunohistochemistry. RESULTS: Treated animals showed enhanced performance on the pasta matrix task relative to sham controls. Increased cell proliferation colabeled with 5'-Bromo-2'-deoxyuridine and neurogenic markers (doublecortin) was observed in the perilesional cortex as well as bilateral mediodorsal and ventrolateral thalamic subnuclei in treated vs untreated animals. The neurogenic effect at the level of motor cortex was selective, with stimulation-treated animals showing greater glutamatergic neurogenesis but significantly less GABAergic neurogenesis. CONCLUSION: These findings suggest that LCN deep brain stimulation modulates postinjury neurogenesis, providing a possible mechanistic foundation for the associated enhancement in poststroke motor recovery.

Crossed Cerebellar Atrophy of the Lateral Cerebellar Nucleus in an Endothelin-1-Induced, Rodent Model of Ischemic Stroke.

Crossed cerebellar diaschisis (CCD) is a functional deficit of the cerebellar hemisphere resulting from loss of afferent input consequent to a lesion of the contralateral cerebral hemisphere. It is manifested as a reduction of metabolism and blood flow and, depending on severity and duration, it can result in atrophy, a phenomenon known as crossed cerebellar atrophy (CCA). While CCA has been well-demonstrated in humans, it remains poorly characterized in animal models of stroke. In this study we evaluated the effects of cerebral cortical ischemia on contralateral cerebellar anatomy using an established rodent model of chronic stroke. The effects of cortical ischemia on the cerebellar hemispheres, vermis and deep nuclei were characterized. Intracortical microinjections of endothelin-1 (ET-1) were delivered to the motor cortex of Long Evans rats to induce ischemic stroke, with animals sacrificed 6 weeks later. Naive animals served as controls. Cerebral sections and cerebellar sections including the deep nuclei were prepared for analysis with Nissl staining. Cortical ischemia was associated with significant thickness reduction of the molecular layer at the Crus 1 and parafloccular lobule (PFL), but not in fourth cerebellar lobule (4Cb), as compared to the ipsilesional cerebellar hemisphere. A significant reduction in volume and cell density of the lateral cerebellar nucleus (LCN), the rodent correlate of the dentate nucleus, was also noted. The results highlight the relevance of corticopontocerebellar (CPC) projections for cerebellar metabolism and function, including its direct projections to the LCN.

Differential frequency modulation of neural activity in the lateral cerebellar nucleus in failed and successful grasps.

The olivo-cerebellar system has an essential role in the detection and adaptive correction of movement errors. While there is evidence of an error signal in the cerebellar cortex and inferior olivary nucleus, the deep cerebellar nuclei have been less thoroughly investigated. Here, we recorded local field potential activity in the rodent lateral cerebellar nucleus during a skilled reaching task and compared event-related changes in neural activity between unsuccessful and successful attempts. Increased low gamma (40-50 Hz) band power was present throughout the reach and grasp behavior, with no difference between successful and unsuccessful trials. Beta band (12-30 Hz) power, however, was significantly increased in unsuccessful reaches, compared to successful, throughout the trial, including during the epoch preceding knowledge of the trial's outcome. This beta band activity was greater in unsuccessful trials of high-performing days, compared to unsuccessful trials of low-performing days, indicating that this activity may reflect an error prediction signal, developed over the course of motor learning. These findings suggest an error-related discriminatory oscillatory hallmark of movement in the deep cerebellar nuclei.

Modulation of Cortical Motor Evoked Potential After Stroke During Electrical Stimulation of the Lateral Cerebellar Nucleus.

BACKGROUND: Deep brain stimulation (DBS) targeting the dentato-thalamo-cortical (DTC) pathway at its origin in the lateral cerebellar nucleus (LCN) has been shown to enhance motor recovery in a rodent model of cortical ischemia. LCN DBS also yielded frequency-specific changes in motor cortex excitability in the normal brain, indexed by motor evoked potential (MEP) amplitude. OBJECTIVE: To investigate the effect of cortical stroke on cortical motor excitability in a rodent ischemia model and to measure the effects of LCN DBS on post-ischemia excitability as a function of stimulation parameters. METHODS: Adult Sprague-Dawley rats were divided into two groups: naïve and stroke, with cortical ischemia induced through multiple, unilateral endothelin-1 injections. All animals were implanted with a bipolar electrode in the LCN opposite the affected hemisphere. MEPs were elicited from the affected hemisphere using intracortical microstimulation (ICMS) techniques. Multiple LCN DBS parameters were examined, including isochronal stimulation at 20, 30, 50, and 100 Hz as well as a novel burst stimulation pattern. RESULTS: ICMS-evoked MEPs were reduced in stroke (n = 10) relative to naïve (n = 12) animals. However, both groups showed frequency-dependent augmentation of cortical excitability in response to LCN DBS. In the naïve group, LCN DBS increased MEPs by 22-58%, while in the stroke group, MEPs were enhanced by 9-41% compared to OFF-DBS conditions. CONCLUSIONS: Activation of the DTC pathway increases cortical excitability in both naïve and post-stroke animals. These effects may underlie, at least partially, functional reorganization and therapeutic benefits associated with chronic LCN DBS in post-stroke animals.

Chronic deep cerebellar stimulation promotes long-term potentiation, microstructural plasticity, and reorganization of perilesional cortical representation in a rodent model.

Control over postinjury CNS plasticity is a major frontier of science that, if conquered, would open new avenues for treatment of neurological disorders. Here we investigate the functional, physiological, and structural changes in the cerebral cortex associated with chronic deep brain stimulation of the cerebellar output, a treatment approach that has been shown to improve postischemia motor recovery in a rodent model of cortical infarcts. Long-Evans rats were pretrained on the pasta-matrix retrieval task, followed by induction of focal cortical ischemia and implantation of a macroelectrode in the contralesional lateral cerebellar nucleus. Animals were assigned to one of three treatment groups pseudorandomly to balance severity of poststroke motor deficits: REGULAR stimulation, BURST stimulation, or SHAM. Treatment initiated 2 weeks post surgery and continued for 5 weeks. At the end, animals were randomly selected for perilesional intracortical microstimulation mapping and tissue sampling for Western blot analysis or contributed tissue for 3D electron microscopy. Evidence of enhanced cortical plasticity with therapeutically effective stimulation is shown, marked by greater perilesional reorganization in stimulation- treated animals versus SHAM. BURST stimulation was significantly effective for promoting distal forepaw cortical representation. Stimulation-treated animals showed a twofold increase in synaptic density compared with SHAM. In addition, treated animals demonstrated increased expression of synaptic markers of long-term potentiation and plasticity, including synaptophysin, NMDAR1, CaMKII, and PSD95. These findings provide a critical foundation of how deep cerebellar stimulation may guide plastic reparative reorganization after nonprogressive brain injury and indicate strong translational potential.

Effects of ketamine and propofol on motor evoked potentials elicited by intracranial microstimulation during deep brain stimulation.

Few preclinical or clinical studies have evaluated the effect of anesthetics on motor evoked potentials (MEPs), either alone or in the presence of conditioning stimuli such as deep brain stimulation (DBS). In this study we evaluated the effects of two commonly used anesthetic agents, propofol and ketamine (KET), on MEPs elicited by intra-cortical microstimulation of the motor cortex in a rodent model with and without DBS of the dentatothalamocortical (DTC) pathway. The effects of propofol anesthesia on MEP amplitudes during DTC DBS were found to be highly dose dependent. Standard, but not high, dose propofol potentiated the facilitatory effects of 30 Hz DTC DBS on MEPs. This facilitation was sustained and phase-dependent indicating that, compared to high dose propofol, standard dose propofol has a beta-band excitatory effect on cortical networks. In contrast, KET anesthetic demonstrated a monotonic relationship with increasing frequencies of stimulation, such that the highest frequency of stimulation resulted in the greatest MEP amplitude. KET also showed phase dependency but less pronounced than standard dose propofol. The results underscore the importance of better understanding the complex effects of anesthetics on cortical networks and exogenous stimuli. Choice of anesthetic agents and dosing may significantly confound or even skew research outcomes, including experimentation in novel DBS indications and paradigms.

Chronic 30-Hz deep cerebellar stimulation coupled with training enhances post-ischemia motor recovery and peri-infarct synaptophysin expression in rodents.

BACKGROUND: Over 500,000 Americans have strokes every year, making stroke the leading cause for disability in the United States and in the industrialized world. New treatments to improve poststroke motor recovery are needed. OBJECTIVE: To investigate a novel approach for enhancing motor recovery that involves chronic, electrical stimulation of ascending cerebellar output combined with motor training. METHODS: Adult Sprague-Dawley rats underwent unilateral endothelin-1 injections in the dominant cerebral cortex and placement of a chronic stimulating electrode in the contralateral lateral cerebellar nucleus. After 1 week, the animals were separated into 2 groups (STIM+ and STIM-), matched for poststroke motor performance in the pasta matrix task. At 2 weeks post-ischemia, the treatment phase was initiated, with animals in the STIM+ group receiving pulsed, 30-Hz stimulation for 12 hours/day. Motor training continued for both groups over 3 to 5 weeks. RESULTS: A total of 23 animals were examined after 3 weeks of treatment. STIM+ animals showed a significant improvement in motor function compared with post-ischemia baseline performance as well as in comparison with the STIM- group. Immunohistochemistry revealed a significant increase in the perilesional expression of synaptophysin for the STIM+ vs the STIM- animals. CONCLUSION: These results indicate that chronic activation of ascending cerebellofugal pathways enhances motor recovery after focal cortical ischemia. The recovery was associated with an increase in perilesional cortical plasticity relative to nontreated controls.

Semi-automated method for estimating lesion volumes.

Accurately measuring the volume of tissue damage in experimental lesion models is crucial to adequately control for the extent and location of the lesion, variables that can dramatically bias the outcome of preclinical studies. Many of the current commonly used techniques for this assessment, such as measuring the lesion volume with primitive software macros and plotting the lesion location manually using atlases, are time-consuming and offer limited precision. Here we present an easy to use semi-automated computational method for determining lesion volume and location, designed to increase precision and reduce the manual labor required. We compared this novel method to currently used methods and demonstrate that this tool is comparable or superior to current techniques in terms of precision and has distinct advantages with respect to user interface, labor intensiveness and quality of data presentation.

Impaired Wheel Running Exercise in CLC-1 Chloride Channel-Deficient Myotonic Mice.

BACKGROUND: Genetic deficiency of the muscle CLC-1 chloride channel leads to myotonia, which is manifested most prominently by slowing of muscle relaxation. Humans experience this as muscle stiffness upon initiation of contraction, although this can be overcome with repeated efforts (the "warm-up" phenomenon). The extent to which CLC-1 deficiency impairs exercise activity is controversial. We hypothesized that skeletal muscle CLC-1 chloride channel deficiency leads to severe reductions in spontaneous exercise. METHODOLOGY/PRINCIPAL FINDINGS: To examine this quantitatively, myotonic CLC-1 deficient mice were provided access to running wheels, and their spontaneous running activity was quantified subsequently. Differences between myotonic and normal mice in running were not present soon after introduction to the running wheels, but were fully established during week 2. During the eighth week, myotonic mice were running significantly less than normal mice (322 ± 177 vs 5058 ± 1253 m/day, P = 0.025). Furthermore, there were considerable reductions in consecutive running times (18.8 ± 1.5 vs 59.0 ± 3.7 min, P < 0.001) and in the distance per consecutive running period (58 ± 38 vs 601 ± 174 m, P = 0.048) in myotonic compared with normal animals. CONCLUSION/SIGNIFICANCE: These findings indicate that CLC-1 chloride deficient myotonia in mice markedly impairs spontaneous exercise activity, with reductions in both total distance and consecutive running times.

Deep brain stimulation of the lateral cerebellar nucleus produces frequency-specific alterations in motor evoked potentials in the rat in vivo.

The cerebral cortex is tightly and reciprocally linked to the cerebellum and the ascending dentato-thalalmo-cortical pathway influences widespread cortical regions. Using a rodent model of middle cerebral artery stroke, we showed previously that chronic, 20 Hz stimulation of the contralateral lateral cerebellar nucleus (LCN) improved motor recovery, while 50 Hz stimulation did not. Using motor evoked potentials (MEP) elicited by intracortical microstimulation, we now show the effect of LCN stimulation on motor cortex excitability as a function of pulse frequency in propofol-anesthetized rats. MEPs were recorded serially, at 15-s intervals, with cerebellar stimulation delivered in 10-min blocks at rates of 20, 30, 40, 50 or 100 Hz. Stimulation at 20, 30, 40 or 50 Hz enhanced the average MEP response across the block, with the maximal overall increase observed during 30 Hz stimulation. However, the effect varied as a function of both repeated trials within the block and LCN stimulation frequency, such that 40 Hz and 50 Hz stimulation showed a reduced effect over time. Stimulation at 100 Hz produced a transient increase in MEP amplitude in some animals; however the overall effect across the block was a trend towards reduced cortical excitability. These results suggest that direct stimulation of the LCN can yield frequency-dependent changes in cortical excitability and may provide a therapeutic approach to modulating cortical activity for the treatment of strokes or other focal cortical lesions, movement disorders and epilepsy.