Chronic Neurology in COVID-19 Era: Clinical Considerations and Recommendations From the REPROGRAM Consortium.

With the rapid pace and scale of the emerging coronavirus 2019 (COVID-19) pandemic, a growing body of evidence has shown a strong association of COVID-19 with pre- and post- neurological complications. This has necessitated the need to incorporate targeted neurological care for this subgroup of patients which warrants further reorganization of services, healthcare workforce, and ongoing management of chronic neurological cases. The social distancing and the shutdown imposed by several nations in the midst of COVID-19 have severely impacted the ongoing care, access and support of patients with chronic neurological conditions such as Multiple Sclerosis, Epilepsy, Neuromuscular Disorders, Migraine, Dementia, and Parkinson disease. There is a pressing need for governing bodies including national and international professional associations, health ministries and health institutions to harmonize policies, guidelines, and recommendations relating to the management of chronic neurological conditions. These harmonized guidelines should ensure patient continuity across the spectrum of hospital and community care including the well-being, safety, and mental health of the patients, their care partners and the health professionals involved. This article provides an in-depth analysis of the impact of COVID-19 on chronic neurological conditions and specific recommendations to minimize the potential harm to those at high risk.

Nerve conduction, circulating osteopontin and taxane-induced neuropathy in breast cancer patients.

OBJECTIVE: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling complication related to taxanes. Underlying mechanisms are not completely understood and no specific treatment exists. We investigated the role of nerve conduction studies (NCS) and of serum osteopontin (OPN) measurement as a means to stratify the risk of developing taxane-induced neuropathy (TIN). METHODS: We enrolled 50 women with breast cancer treated with taxanes (docetaxel or paclitaxel) in a 3-month prospective study. They were evaluated before chemotherapy (time-point T0) and followed up at 1 (T1) and 3 (T2) months with clinical examinations/scales, quality of life (QoL) questionnaires, NCS, and serum OPN dosages. RESULTS: A reduction of sural and superficial peroneal sensory action potentials was seen at T1, with a progression at T2 (P<0.001). In contrast, a significant impact of neuropathic symptoms on QoL only occurred at T2 (P<0.01). OPN levels at T0 inversely correlated to axonal loss in the sural nerve (T0-T2, P<0.01). OPN levels at T0 were lower in the intermediate and poor outcome patient subgroups, compared to the good outcome subgroup, as specifically defined (P<0.05). CONCLUSION: Lower limb NCS changes occurred earlier than the detrimental effects of TIN on patients' QoL. Low serum OPN levels before chemotherapy may represent a novel biomarker of TIN risk.

Chronic obstructive pulmonary disease may complicate Alzheimer's disease: a comorbidity problem.

BACKGROUND AND AIM: Chronic obstructive pulmonary disease (COPD) may be associated with worsening of cognitive performance. We studied patients with Alzheimer's disease (AD) with and without COPD, and we analyzed, in a retrospective way, clinical and neuropsychological variables to verify if COPD plays a pejorative role on cognitive or functional autonomy in patients with dementia. METHODS: We enrolled 23 adult patients (AD-COPD) with probable AD and COPD and 23 with AD only (AD-only); they were matched for sex, age, educational level, and Mini Mental State Examination (MMSE) at the disease onset. Global cognitive status was estimated using MMSE at the first assessment and after 24 months. Memory, executive functions, praxia, and language were the other cognitive domains analyzed. The two groups were also compared for the presence of behavioral disorders (anxiety, depression). RESULTS: AD-COPD had worse results in executive functions screening than AD-only; no significant differences were found comparing other cognitive domains; moreover, there was no significant difference between the two groups considering the decrease in MMSE scores. AD-COPD also showed a higher presence of depression. DISCUSSION: COPD is known to be associated with the development of cognitive deficits, in particular, regarding for executive functions and attention, memory and logical reasoning. In this context, MMSE has a low diagnostic accuracy to underline effective cognitive impairment in AD-COPD. Our study shows a higher frequency of frontal deficits and behavioral disturbances in patients with AD and COPD than patients with AD-only. COPD could complicate the management of AD patients, thus necessitating a closer and multidisciplinary monitoring.

Human neural stem cell transplantation in ALS: initial results from a phase I trial.

BACKGROUND: We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board. METHODS: Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials. RESULTS: No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease. CONCLUSIONS: We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material. TRIAL REGISTRATION: EudraCT:2009-014484-39 .

Botulinum toxin injection into the forearm muscles for wrist and fingers spastic overactivity in adults with chronic stroke: a randomized controlled trial comparing three injection techniques.

OBJECTIVE: To compare the outcome of manual needle placement, electrical stimulation and ultrasonography-guided techniques for botulinum toxin injection into the forearm muscles of adults with arm spasticity. DESIGN: Randomized controlled trial. SETTING: University hospital. SUBJECTS: Sixty chronic stroke patients with wrist and fingers spasticity. INTERVENTION: After randomization into three groups, each patient received botulinum toxin type A in at least two of these muscles: flexor carpi radialis and ulnaris, flexor digitorum superficialis and profundus (no fascicles selection). The manual needle placement group underwent injections using palpation; the electrical stimulation group received injections with electrical stimulation guidance; the ultrasonography group was injected under sonographic guidance. A sole injector was used. MAIN MEASURES: All patients were evaluated at baseline and four weeks after injection. OUTCOMES: Modified Ashworth Scale; Tardieu Scale; wrist and fingers passive range of motion. RESULTS: One month after injection, Modified Ashworth Scale scores improved more in the electrical stimulation group than the manual needle placement group (wrist: P = 0.014; fingers: P = 0.011), as well as the Tardieu angle (wrist: P = 0.008; fingers: P = 0.015) and passive range of motion (wrist: P = 0.004). Furthermore, Modified Ashworth Scale scores improved more in the ultrasonography group than in the manual needle placement group (wrist: P = 0.001; fingers: P = 0.003), as well as the Tardieu angle (wrist: P = 0.010; fingers: P = 0.001) and passive range of motion (wrist: P < 0.001; proximal interphalangeal joints: P = 0.009). No difference was found between the ultrasonography and electrical stimulation groups. CONCLUSIONS: Instrumental guidance may improve the outcome of botulinum toxin injections into the spastic forearm muscles of stroke patients.

Defective visual inhibition in photosensitive idiopathic generalized epilepsy.

PURPOSE: To assess the visual system excitability of photosensitive patients with idiopathic generalized epilepsy (IGE) with the paired-pulse flash-evoked potential (paired F-VEP) technique. METHODS: We studied 19 photosensitive patients with IGE (16 women) showing a photoparoxysmal electroencephalographic (EEG) response (PPR). Twenty-two normal subjects of similar age and sex acted as controls (17 women). We recorded F-VEPs from occipital and central electrodes. Stimuli were single flashes, intermingled to flash pairs at the interstimulus interval (ISI) of 333, 125, 62.5, 50, 33, and 16.5 msec (i.e., at the internal frequency of 3, 8, 16, 20, 30, and 60 Hz). Recordings were done both with closed and open eyes. The single F-VEP was split into a "main complex" and a "late response," which were measured separately. As to paired stimuli, the "test" F-VEP emerged from electronic subtraction of the single F-VEP to the paired F-VEP. Grouped data were analyzed by means of nonparametric analyses of variance (ANOVAs). KEY FINDINGS: In patients, the single F-VEP showed some enhanced components in its early "main complex." Then, the "test" F-VEP behaved differently than controls, particularly if recorded with closed eyes, when the normal inhibition was abolished at given ISIs, corresponding to an internal frequency of 16-30 Hz. In patients with a posterior PPR, impaired inhibition was evident over the occipital region only, but in those with a widespread PPR, it also involved the central areas. SIGNIFICANCE: The paired F-VEP technique documents a defective inhibition in the visual system of photosensitive patients with IGE, whose features and timing likely underlie the PPR origin.

Cortical excitability changes associated with fixation-off sensitivity: a case report.

"Fixation-off sensitivity" (FOS) is an ideal human model for studying the features of epileptic discharges. Physiologically, FOS is expected to correspond to enhanced excitability of widespread cortical structures. To test this hypothesis, we measured by transcranial magnetic stimulation (TMS), the excitability level of the primary motor area in a 22-year-old woman with eyelid myoclonias and absences, who presented with generalized FOS. We also explored her visual system by pattern-reversal and flash-visual evoked potentials (VEPs). Both outside and within FOS, the cortical silent period was dramatically short, indicating defective γ-aminobutyric acid (GABA)(B) inhibition as a persistent background factor. The same was true for the short-interval intracortical inhibition, a TMS marker of cortical GABA(A) inhibition. The FOS state corresponded then to a pathologic enhancement of intracortical facilitation, a TMS marker of Glu/Asp transmission. During FOS, the flash VEP exhibited a hugely enhanced afterdischarge, expressing a pathologic overactivity of secondary visual areas. Within the limits of a single-case study, we thus provide electrophysiologic evidence supporting a grossly imbalanced cortical excitability, in both the frontal and posterior areas, as an important correlate of the present FOS subtype.

Paired-pulse flash-visual evoked potentials: new methods revive an old test.

OBJECTIVE: We aimed at reviving with modern technology the paired flash-visual evoked potential (F-VEP) testing of the visual system excitability. In the 1960s, methodological problems hindered this test, which was expected to provide important physiologic information. METHODS: We studied 22 consenting healthy subjects (10 men). We recorded F-VEPs from electrodes over occipital and central brain regions. We delivered single flashes, mixed at random to flash pairs at the interstimulus interval (ISI) of 333, 125, 62.5, 50, 33, and 16.5 ms, (i.e. an internal frequency (IF) of 3, 8, 16, 20, 30, and 60 Hz). Recordings were performed with the subject's eyes closed and opened. The F-VEP was split into a "main complex" and an "afterdischarge", which we analyzed statistically in relation to the eye state (closed or open) and to the changes due to paired stimulation. RESULTS: The eye state affected the single F-VEP size, latency and shape significantly (p<0.05). On paired stimulation, the test (second) F-VEP exhibited significant (p<0.05), ISI-dependent size changes, such as a progressive decrease for ISIs from 62.5 to 16.5 ms (IFs of 16-60 Hz), whose timing/amount varied significantly (p<0.05) according to the eye state and to the F-VEP epoch considered. Suppression of the test F-VEP was never complete, even for the shortest ISI (ISI=16.5 ms, IF=60 Hz). CONCLUSIONS: The eye state (closed or open) must be considered meticulously when studying F-VEPs. F-VEP changes on paired stimulation express neural inhibition within the visual system, which can be depicted as ISI-dependent curves. SIGNIFICANCE: Modern equipment and simplified measures render this an easy test, with statistical validity, providing specific information on the excitability properties of the visual system.

Complex pattern of convulsive syncope in glossopharyngeal neuralgia: video/EEG report and short review.

A 65-year-old woman presented with three "convulsive" events that were preceded by stabbing pain extending from the left submandible zone to the neck and ipsilateral ear. Video-electroencephalography captured a typical attack, where electrocardiography showed bradycardia for 17 seconds and asystole for at least 9 seconds. The patient lost consciousness while her head/gaze turned right. She then manifested tonic extension of her left limbs followed by adduction of her left limb and flexion of her right upper limb. Her gaze deviated upward and her left upper limb manifested swimming-like automatisms. The full episode lasted about 70 seconds, and the EEG showed progressive diffuse high-amplitude slowing. A diagnosis of convulsive syncope resulting from classic glossopharyngeal neuralgia was made. Carbamazepine led to steady remission. Glossopharyngeal neuralgia is a rare condition (incidence of 0.7/100.000/year), whereas the occurrence of syncope is about 20%, and that of convulsive syncope is about 5%.