Multifocal Transcranial Direct Current Stimulation in Primary Progressive Aphasia Does Not Provide a Clinical Benefit Over Speech Therapy.

BACKGROUND: Primary progressive aphasia (PPA) is a group of neurodegenerative disorders including Alzheimer's disease and frontotemporal dementia characterized by language deterioration. Transcranial direct current stimulation (tDCS) is a non-invasive intervention for brain dysfunction. OBJECTIVE: To evaluate the tolerability and efficacy of tDCS combined with speech therapy in the three variants of PPA. We evaluate changes in fMRI activity in a subset of patients. METHODS: Double-blinded, randomized, cross-over, and sham-controlled tDCS study. 15 patients with PPA were included. Each patient underwent two interventions: a) speech therapy + active tDCS and b) speech therapy + sham tDCS stimulation. A multifocal strategy with anodes placed in the left frontal and parietal regions was used to stimulate the entire language network. Efficacy was evaluated by comparing the results of two independent sets of neuropsychological assessments administered at baseline, immediately after the intervention, and at 1 month and 3 months after the intervention. In a subsample, fMRI scanning was performed before and after each intervention. RESULTS: The interventions were well tolerated. Participants in both arms showed clinical improvement, but no differences were found between active and sham tDCS interventions in any of the evaluations. There were trends toward better outcomes in the active tDCS group for semantic association and reading skills. fMRI identified an activity increase in the right frontal medial cortex and the bilateral paracingulate gyrus after the active tDCS intervention. CONCLUSION: We did not find differences between active and sham tDCS stimulation in clinical scores of language function in PPA patients.

Adaptation to tonic heat in healthy subjects and patients with sensory polyneuropathy.

Background Adaptation to a constant sensory stimulus involves many sites along the path of sensory volleys towards perception. The evaluation of such phenomenon may be of clinical interest. We studied adaptation to a constant temperature stimulus in healthy subjects to set normative data and in patients with sensory polyneuropathy (SPN), as proof of concept. Methods Twenty-six healthy subjects and 26 patients with SPN in the context of chemotherapy treatment with oxaliplatin for colon cancer were instructed to express through an electronic VAS system (eVAS); the level of sensation felt when a thermode set at either 39º, 41º, 43º, 45º or 47º was applied to their ventral forearm. Results The eVAS recordings showed typically an abrupt onset that slowed to approach maximum sensation and continued with a slow decrease indicating adaptation. The time to respond (TR), the velocity of the initial response (VR), the maximum sensation (MA), the time to reach MA (MAt), the onset of adaptation (AO) and the decrease in the sensation level with respect to MA at 30 s after stimulus application (SL30), were dependent on the temperature level in all subjects. However, patients showed significantly delayed TR, slowed VR, decreased MA, delayed AO and reduced SL30, with respect to healthy subjects. Differences were more pronounced at low-temperature levels, with absent AO in 25 patients versus 2 healthy subjects at temperatures of 39º and 41ºC. Conclusion The study of adaptation to a constant temperature stimulus can furnish valuable data for the assessment of patients with SPN. SIGNIFICANCE: We studied perceptual changes in the intensity of thermoalgesic sensation during 30 s of constant temperature stimulation after an abrupt initial contact in healthy subjects and patients with sensory polyneuropathy. Patients showed delayed time to respond, decreased maximal sensation and reduced adaptation with respect to healthy subjects. Differences were more pronounced at low and intermediate temperatures (39ºC to 43ºC). The method is of easy implementation and shows clinically relevant abnormalities in patients with sensory polyneuropathy.

Prognostic value of cutaneous reinnervation with GAP-43 in oxaliplatin-induced neuropathy.

BACKGROUND AND PURPOSE: Oxaliplatin-induced neuropathy (OIN) implies axonal damage of both small and large sensory nerve fibers. We aimed at comparing the neurophysiological changes occurred after treatment and the capability to recovery based on histological marker of re-innervation GAP-43. METHODS: 48 patients with cancer were assessed before and after chemotherapy (at 3 months and 12 months if available). We recorded ulnar and sural sensory nerve action potentials (SNAP), determined quantitative sensory thresholds for warm and cold (WDT, CDT), pain thresholds and collected a distal biopsy of skin to assess the intra-epidermal nerve fiber density (IENFD) with PGP9.5 and GAP-43 markers (in a subgroup of 19 patients). RESULTS: Increased WDT and CDT as well as diminished IENFD at distal leg were already found in 30% of oncologic patients before treatment. After oxaliplatin, there was a significant increase in thermal thresholds in 52% of patients, and a decrease of SNAP amplitude in the sural nerve in 67% patients. IENFD was reduced in 47% and remained unchanged in 37% after oxiplatin. The density of GAP-43 + fibers and GAP-43/PGP 9.5 ratio was similar before and after treatment showing that cutaneous re-innervation is preserved despite no clinical recovery was observed after one year. CONCLUSION: Non-selective axonal loss affects sensory fibers in OIN. However, the presence of intra-epidermal regenerative sprouts detected by GAP-43 may reduce the impact of neurotoxicity in the small fibers with long-term sequelae mostly on myelinated nerve endings. Pre-oxaliplatin GAP-43 failed to identify patients with higher risk of damage or worse recovery after treatment.

Electrodiagnostic Testing of Small Fiber Neuropathies: A Review of Existing Guidelines.

This article reviews the literature on neurophysiological techniques for the diagnosis of small fiber neuropathy. The review is focused on clinical approach to suspected small fiber neuropathy, letting aside techniques whose clinical applicability is doubtful. We include, however, the special techniques required to examine C and Aδ fibers, which cannot be evaluated directly with conventional neurophysiological methods. The most relevant publications are summarized and recommendations for the clinical assessment of small fiber neuropathy are provided.

Acute lumbar polyradiculoneuropathy as early sign of methotrexate intrathecal neurotoxicity: Case report and literature review.

Acute paraplegia after treatment with intrathecal methotrexate requires a complete spinal cord neuroimaging as well as electrodiagnostic examination. The absence of lumbosacral F waves motor responses without demyelinating findings may indicate early direct root toxicity. Early electromyography (EMG) screening could be a valuable tool for detecting peripheral neurotoxicity.

Thermoalgesic stimuli induce prepulse inhibition of the blink reflex and affect conscious perception in healthy humans.

All sensory stimuli produce transient excitability changes in various central nervous system circuits. One example is prepulse inhibition (PPI), which is the inhibition generated by a preceding weak stimulus (prepulse) over the reflex response to a subsequent suprathreshold stimulus. The PPI is a ubiquitous phenomenon, common to many different sensory modalities. However, it has not yet been studied with thermoalgesic stimuli. These stimuli take a relatively long time to reach their peak, which implies some uncertainty in the exact timing of prepulse effects with respect to stimulus onset. In 20 healthy volunteers, we determined when thermoalgesic stimuli cause PPI of the blink reflex and measured conscious awareness (AW) of thermoalgesic stimulus perception using the Libet's clock. In this way, we determined the temporal relationship between AW and PPI. In a second experiment, we investigated whether prepulse effects on blink reflex also involved a change in conscious perception of the supraorbital nerve stimulus. Our results show that thermoalgesic stimuli generate PPI of the blink reflex long before subjects were consciously aware of the stimulus, confirming the already-known principle that conscious perception is not required for PPI to take place, and that prepulse stimuli induce a change in the time of conscious perception of prepulse and pulse stimuli, in such a way that AW of both stimuli tended to become closer to each other.

Evidence of neurophysiological improvement of early manifestations of small-fiber dysfunction after liver transplantation in a patient with familial amyloid neuropathy.

INTRODUCTION: Small fiber polyneuropathy (SFP) is a common heralding clinical manifestation of damage to the nervous system in patients with familial amyloidosis. The diagnosis of SFP is a significant factor in the decision to treat a previously asymptomatic gene carrier, as treatment would prevent irreversible nerve damage. This requires detection of the earliest but unequivocal signs of peripheral nerve involvement. CASE REPORT: We present the case of a young female who was diagnosed of SFP, supported by data from quantitative sensory testing. She had preserved sensory nerve action potentials in the distalmost nerves of her feet and recordable nociceptive evoked potentials. She was successfully transplanted the liver from a previously healthy donor, and recovered fully of her symptoms and signs. Improvement was documented with repeated psychophysical and electrodiagnostic testing in the course of 4 years after transplantation. SIGNIFICANCE: This case illustrates the utility of psychophysical testing to support the diagnosis of SFP.

Clinical utility of contact heat evoked potentials (CHEPs) in a case of mentalis nerve lesion.

OBJECTIVE: Nociceptive evoked potentials are still infrequently used in electrodiagnostic studies of single patients. We report a case in which the results of contact heat evoked potentials (CHEPs) provided unique information for the diagnosis. METHODS: After biopsy for a local cementoma, a 21-year-old woman presented with neuropathic pain in the distribution of her left mentalis nerve. A CT scan showed a well circumscribed lesion near the mentalis nerve groove. We examined brainstem reflexes and evoked potentials conveyed through the mentalis nerve. RESULTS: Blink reflex responses recorded from the orbicularis oculi, jaw jerk and masseteric silent period recorded from the masseter muscles and long latency evoked potentials recorded from Cz to electrical stimulation of the mentalis nerve were all within normal values, with no differences between sides. However, CHEPs, recorded from Cz to thermoalgesic stimulation of the left mentalis area were decreased to approximately 1/3 their size in comparison to stimulation to the unaffected side. CONCLUSION: While the patient reported symptoms and had neuroimaging signs of mentalis neuropathy, the sole electrophysiological abnormality identified was that of CHEPs, which specifically test small, unmyelinated fibers. SIGNIFICANCE: Nociceptive evoked potentials can provide unique information on damage of small nerve fibers in specific cases.

Motor preparation in picture naming tasks.

In certain circumstances, words can be uttered as an involuntary action. We hypothesize that, once pronunciation of a word is fully prepared it can be triggered as a reflex with no need for cortical processing. We used modified protocols of picture naming tasks, with different levels of cognitive demands, to measure reaction time to word pronunciation (RTWP). In test trials, picture presentation was accompanied by a startling auditory stimulus (SAS). When one and the same picture was repeatedly shown, SAS shortened RTWP by about 30% (StartReact effect), which did not occur when random pictures were shown. If subjects were led to learn which picture was to appear after repeated presentation of three pictures in sequence, they exhibited again the StartReact effect. We conclude that word pronunciation may be fully prepared for execution in absence of cognitive demands. However, the StartReact effect is inhibited during cognitive tasks.

Motor polyradiculopathy during pembrolizumab treatment of metastatic melanoma.

INTRODUCTION: Pembrolizumab, a monoclonal antibody directed against the immune checkpoint programmed cell death-1 receptor (PD-1), has improved survival in patients with advanced melanoma. Neuromuscular immune-mediated side effects have been rarely reported. METHODS: We describe a 44-year-old man with metastatic melanoma who presented with progressive muscle weakness after 23 doses of pembrolizumab. RESULTS: The patient developed asymmetric, proximal muscle weakness and atrophy in all four limbs. Cerebrospinal fluid examination showed albuminocytologic dissociation. MRI revealed contrast enhancement of the lumbosacral roots. Electrodiagnostic studies demonstrated widespread fibrillation potentials in all four limbs, suggesting a generalized motor polyradiculopathy. Despite pembrolizumab discontinuation and treatment with steroids and intravenous immunoglobulin, limb weakness worsened. Electrodiagnostic studies were repeated, and showed marked and diffuse axonal motor damage. Seven weeks after clinical onset the patient was treated with plasma exchanges. He showed no further deterioration. DISCUSSION: We report a severe motor polyradiculopathy associated with an anti-PD-1 agent that expands the spectrum of neuromuscular complications of this class of drugs. Muscle Nerve 56: E162-E167, 2017.

Stimulus waveform determines the characteristics of sensory nerve action potentials.

OBJECTIVE: In routine nerve conduction studies supramaximal electrical stimuli generate sensory nerve action potentials by depolarization of nerve fibers under the cathode. However, stimuli of submaximal intensity may give rise to action potentials generated under the anode. We tested if this phenomenon depends on the characteristics of stimulus ending. METHODS: We added a circuit to our stimulation device that allowed us to modify the end of the stimulus by increasing the time constant of the decay phase. RESULTS: Increasing the fall time caused a reduction of anode action potential (anAP) amplitude, and eventually abolished it, in all tested subjects. We subsequently examined the stimulus waveform in a series of available electromyographs stimulators and found that the anAP could only be obtained with stimulators that issued stimuli ending sharply. CONCLUSION: Our results prove that the anAP is generated at stimulus end, and depends on the sharpness of current shut down. Electromyographs produce stimuli of varying characteristics, which limits the reproducibility of anAP results by interested researchers. SIGNIFICANCE: The study of anodal action potentials might be a useful tool to have a quick appraisal of distal human sensory nerve excitability.

Effects of postural and voluntary muscle contraction on modulation of the soleus H reflex by transcranial magnetic stimulation.

Modulation of spinal reflexes depends largely on the integrity of the corticospinal tract. A useful method to document the influence of descending tracts on reflexes is to examine the effects of transcranial magnetic stimulation (TMS) on the soleus H reflex elicited by posterior tibial nerve electrical stimuli (PTS). In 12 healthy volunteers, we investigated how postural or voluntary muscle contraction modified such descending modulation. We first characterized the effects of TMS at 95 % of motor threshold for leg responses on the H reflex elicited by a preceding PTS at inter-stimuli intervals (ISIs) between 0 and 120 ms at rest and, then, during voluntary plantar flexion (pf), dorsal flexion (df), and standing still (ss). During pf, there was an increase in the facilitation of the H reflex at ISIs 0-20 ms. During df, there were no effects of TMS on the H reflex. During ss, there was inhibition at ISIs 40-60 ms. Our observations suggest that muscle contraction prevails over the baseline effects of TMS on the soleus H reflex. While contraction of the antagonist (df) suppressed most of the effects, contraction of the agonist had different effects depending on the type of activity (pf or ss). The characterization of the interaction between descending corticospinal volleys and segmental peripheral inputs provides useful information on motor control for physiological research and further understanding of the effects of spinal cord lesions.

Cutaneous autonomic denervation in Parkinson's disease.

Numerous studies have detailed involvement of the peripheral autonomic nervous system (PANS) in Parkinson's disease (PD). We assessed autonomic innervation of dermal annexes through quantitative fluorescence measurement from skin obtained via punch biopsies at distal leg region in PD and control subjects. We defined a ratio between the area corresponding to protein gen product (PGP) immunoreactivity and the area corresponding to blood vessel or sweat gland as a quantitative measure of autonomic innervation. Presence of alpha-synuclein (AS) deposits in dermis and hypodermis was also assessed by immunohistochemistry. Skin biopsies form six PD patients and six healthy controls were studied. Autonomic innervation scores were lower in PD than in controls in both blood vessels and sweat glands. No AS or phosphorylated AS (pAS) immunoreactivity was detected in dermis or hypodermis in any of the studied subjects. The results of this investigation suggest that autonomic innervation of dermal annexes in living patients with PD is reduced compared to controls. AS or pAS deposits were not found in dermis or hypodermis suggesting that distal leg skin study is not useful for in vivo detection of AS in PD.

Defective sensorimotor integration in preparation for reaction time tasks in patients with multiple sclerosis.

Slowness of voluntary movements in patients with multiple sclerosis (MS) may be due to various factors, including attentional and cognitive deficits, delays in motor conduction time, and impairment of specific central nervous system circuits. In 13 healthy volunteers and 20 mildly disabled, relapsing-remitting MS patients, we examined simple reaction time (SRT) tasks requiring sensorimotor integration in circuits involving the corpus callosum and the brain stem. A somatosensory stimulus was used as the imperative signal (IS), and subjects were requested to react with either the ipsilateral or the contralateral hand (uncrossed vs. crossed SRT). In 33% of trials, a startling auditory stimulus was presented together with the IS, and the percentage reaction time change with respect to baseline SRT trials was measured (StartReact effect). The difference between crossed and uncrossed SRT, which requires interhemispheric conduction, was significantly larger in patients than in healthy subjects (P = 0.021). The StartReact effect, which involves activation of brain stem motor pathways, was reduced significantly in patients with respect to healthy subjects (uncrossed trials: P = 0.015; crossed trials: P = 0.005). In patients, a barely significant correlation was found between SRT delay and conduction abnormalities in motor and sensory pathways (P = 0.02 and P = 0.04, respectively). The abnormalities found specifically in trials reflecting interhemispheric transfer of information, as well as the evidence for reduced subcortical motor preparation, indicate that a delay in reaction time execution in MS patients cannot be explained solely by conduction slowing in motor and sensory pathways but suggest, instead, defective sensorimotor integration mechanisms in at least the two circuits examined.

Disturbed sensory perception of changes in thermoalgesic stimuli in patients with small fiber neuropathies.

The assessment of functional deficits in small fibre neuropathies (SFN) requires using ancillary tests other than conventional neurophysiological techniques. One of the tests with most widespread use is thermal threshold determination, as part of quantitative sensory testing. Thermal thresholds typically reflect one point in the whole subjective experience elicited by a thermal stimulus. We reasoned that more information could be obtained by analyzing the subjective description of the ongoing sensation elicited by slow temperature changes (dynamic thermal testing, DTT). Twenty SFN patients and 20 healthy subjects were requested to describe, by using an electronic visual analog scale system, the sensation perceived when the temperature of a thermode was made to slowly change according to a predetermined pattern. The thermode was attached to the left ventral forearm or the distal third of the left leg and the stimulus was either a monophasic heat or cold stimuli that reached 120% of pain threshold and reversed to get back to baseline at a rate of 0.5 °C/s. Abnormalities seen in patients in comparison to healthy subjects were: (1) delayed perception of temperature changes, both at onset and at reversal, (2) longer duration of pain perception at peak temperature, and (3) absence of an overshoot sensation after reversal, ie, a transient perception of the opposite sensation before the temperature reached again baseline. The use of DTT increases the yield of thermal testing for clinical and physiological studies. It adds information that can be discriminant between healthy subjects and SFN patients and shows physiological details about the process of activation and inactivation of temperature receptors that may be abnormal in SFN.

Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case-control study.

BACKGROUND: Fabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy. We set out to investigate small fiber conduction in Fabry patients using pain-related evoked potentials (PREP). METHODS: In this case-control study we prospectively studied 76 consecutive Fabry patients for electrical small fiber conduction in correlation with small fiber function and morphology. Data were compared with healthy controls using non-parametric statistical tests. All patients underwent neurological examination and were investigated with pain and depression questionnaires. Small fiber function (quantitative sensory testing, QST), morphology (skin punch biopsy), and electrical conduction (PREP) were assessed and correlated. Patients were stratified for gender and disease severity as reflected by renal function. RESULTS: All Fabry patients (31 men, 45 women) had small fiber neuropathy. Men with Fabry disease showed impaired cold (p < 0.01) and warm perception (p < 0.05), while women did not differ from controls. Intraepidermal nerve fiber density (IENFD) was reduced at the lower leg (p < 0.001) and the back (p < 0.05) mainly of men with impaired renal function. When investigating A-delta fiber conduction with PREP, men but not women with Fabry disease had lower amplitudes upon stimulation at face (p < 0.01), hands (p < 0.05), and feet (p < 0.01) compared to controls. PREP amplitudes further decreased with advance in disease severity. PREP amplitudes and warm (p < 0.05) and cold detection thresholds (p < 0.01) at the feet correlated positively in male patients. CONCLUSION: Small fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity. PREP are well-suited to measure A-delta fiber conduction.