Hela G. Zouari

Diagnosis of small fiber neuropathy: A comparative study of five neurophysiological tests.

The diagnosis of small fiber neuropathy (SFN) is a challenge for clinical neurophysiology. Conventional nerve conduction studies are inappropriate for this purpose and therefore various neurophysiological tests have been proposed. In this study, we compared the diagnostic value of five of these tests in 87 patients with clinically definite (n=33) or possible (n=54) SFN related to amyloid neuropathy secondary to transthyretin gene mutation or monoclonal gammopathy (n=30), primary Sjögrens syndrome (n=20), Fabrys disease (n=2), or unknown cause (n=35). Neurophysiological tests included quantitative sensory testing with determination of warm and cold detection thresholds (WDT, CDT), recording of laser-evoked potentials (LEP) and sympathetic skin responses (SSRs), and measurement of electrochemical skin conductance (ESC) using Sudoscan(®) device. All tests were performed at the four extremities (hands and feet). All patients with clinically definite SFN and 70% of the patients with possible SFN had at least one abnormal test. The LEP was the most sensitive test (altered in 79% of the patients with at least one abnormal test), followed by ESC (61%), WDT (55%), SSR (41%), and CDT (32%). The combination of LEP, assessing A-delta sensory fibers, WDT, assessing sensory C fibers, and ESC, assessing autonomic C fibers, appears a relevant approach for the diagnosis of SFN. Compared to SSR and CDT, these three tests, LEP, WDT, and ESC, had a significantly better diagnostic sensitivity and their combination further improved diagnostic accuracy.

Stroke rehabilitation using noninvasive cortical stimulation: motor deficit

Noninvasive cortical stimulation (NICS) has been used during the acute, postacute and chronic poststroke phases to improve motor recovery in stroke patients having upper- and/or lower-limb paresis. This paper reviews the rationale for using the different NICS modalities to promote motor stroke rehabilitation. The changes in cortical excitability after stroke and the possible mechanisms of action of cortical stimulation in this context are outlined. A number of open and placebo-controlled trials have investigated the clinical effect of repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) of the primary motor cortex in patients with motor stroke. These studies attempted to improve motor performance by increasing cortical excitability in the stroke-affected hemisphere (via high-frequency rTMS or anodal tDCS) or by decreasing cortical excitability in the contralateral hemisphere (via low-frequency rTMS or cathodal tDCS). The goal of these studies was to reduce the inhibition exerted by the unaffected hemisphere on the affected hemisphere and to then restore a normal balance of interhemispheric inhibition. All these NICS techniques administered alone or in combination with various methods of neurorehabilitation were found to be safe and equally effective at the short term on various aspects of poststroke motor abilities. However, the long-term effect of NICS on motor stroke needs to be further evaluated before considering the use of such a technique in the daily routine management of stroke.

Relapses in multiple sclerosis: effects of high-dose steroids on cortical excitability

High‐dose steroid administration is the usual treatment of multiple sclerosis (MS) relapse, but it remains to determine whether this treatment may act by changing the excitability of cortical circuitry.

Stroke rehabilitation using noninvasive cortical stimulation: hemispatial neglect

The rehabilitation of neuropsychological sequels of cerebral stroke such as hemispatial neglect by noninvasive cortical stimulation (NICS) attracts increasing attention from the scientific community. The NICS techniques include primarily repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). They are based on the concept of either reactivating a hypoactive cortical region affected by the stroke (the right hemisphere in case of neglect) or reducing cortical hyperactivity of the corresponding cortical region in the contralateral hemisphere (the left hemisphere). In the studies published to date on the topic of neglect rehabilitation, rTMS was used to inhibit the left parietal cortex and tDCS to either activate the right or inhibit the left parietal cortex. Sham-controlled NICS studies assessed short-term effects, whereas long-term effects were only assessed in noncontrolled rTMS studies. Further controlled studies of large series of patients are necessary to determine the best parameters of stimulation (including the optimal cortical target location) according to each subtype of neglect presentation and to the time course of stroke recovery. To date, even if there are serious therapeutic perspectives based on imaging data and experimental studies, the evidence is not compelling enough to recommend any particular NICS protocol to treat this disabling condition in clinical practice.

Stroke rehabilitation using noninvasive cortical stimulation: aphasia

Poststroke aphasia results from the lesion of cortical areas involved in the motor production of speech (Broca’s aphasia) or in the semantic aspects of language comprehension (Wernicke’s aphasia). Such lesions produce an important reorganization of speech/language-specific brain networks due to an imbalance between cortical facilitation and inhibition. In fact, functional recovery is associated with changes in the excitability of the damaged neural structures and their connections. Two main mechanisms are involved in poststroke aphasia recovery: the recruitment of perilesional regions of the left hemisphere in case of small lesion and the acquisition of language processing ability in homotopic areas of the nondominant right hemisphere when left hemispheric language abilities are permanently lost. There is some evidence that noninvasive cortical stimulation, especially when combined with language therapy or other therapeutic approaches, can promote aphasia recovery. Cortical stimulation was mainly used to either increase perilesional excitability or reduce contralesional activity based on the concept of reciprocal inhibition and maladaptive plasticity. However, recent studies also showed some positive effects of the reinforcement of neural activities in the contralateral right hemisphere, based on the potential compensatory role of the nondominant hemisphere in stroke recovery.

Tremor in multiple sclerosis: The intriguing role of the cerebellum

Tremor is frequently encountered in multiple sclerosis (MS) patients. However, its underlying pathophysiological mechanisms remain poorly understood. Our aim was to assess the potential role of the cerebellum and brain stem structures in the generation of MS tremor.We performed accelerometric (ACC) and electromyographic(EMG) assessment of tremor in 32MS patients with manual clumsiness. In addition to clinical examination, patients underwent a neurophysiological exploration of the brainstem and cerebellar functions,which consisted of blink and masseter inhibitory reflexes, cerebello-thalamo-cortical inhibition (CTCi), and somatosensory evoked potentials. Tremor was clinically visible in 18 patients and absent in 14. Patients with visible tremor had more severe score of ataxia and clinical signs of cerebellar dysfunction, as well as a more reduced CTCi on neurophysiological investigation. However, ACC and EMG recordings confirmed the presence of a real rhythmic activity in only one patient. In most MS patients, the clinically visible tremor corresponded to a pseudorhythmic activity without coupling between ACC and EMG recordings. Cerebellar dysfunction may contribute to the occurrence of this pseudorhythmic activity mimicking tremor during posture and movement execution.

A reappraisal of small- and large-fiber damage in carpal tunnel syndrome: New insights into the value of the EMLA test for improving diagnostic sensitivity

OBJECTIVES To reappraise the respective involvement of small- and large-fiber damage in carpal tunnel syndrome (CTS) and to determine the diagnostic sensitivity of autonomic tests compared to conventional nerve conduction study (NCS). METHODS Thirty-two manual workers complaining of at least unilateral CTS were enrolled. They underwent clinical interview and completed the symptom severity scale of the Boston CTS Questionnaire (sssBCTQ) and the Neuropathic Pain Symptom Inventory (NPSI). In addition, transcarpal NCS was performed to investigate large sensory and motor fibers of the median nerve, while small autonomic fibers were assessed by recording sympathetic skin reflexes (SSR) at the palm and by grading skin wrinkling in response to eutectic mixture of local anesthetic (EMLA) cream application at the pulp of the index finger. For each neurophysiological variable, sensitivity and specificity values for the diagnosis of CTS were calculated and clinical correlations were studied. RESULTS Among 64 hands examined, 36 were clinically symptomatic, while 22 were clinically asymptomatic and served as controls. Among all the neurophysiological variables studied, only the values of transcarpal sensory nerve conduction velocity and the EMLA test grade were found to be more altered in clinically symptomatic hands, with also a trend towards prolonged distal motor latency. Overall, for the diagnosis of clinically symptomatic CTS, NCS, SSR, and the EMLA test had a sensitivity of 66.7%, 22.2%, and 69.4%, respectively, and a specificity of 72.7%, 90.9%, and 50%, respectively. Combining NCS and the EMLA test led to a sensitivity of 88.9% and a specificity of 45.4%. The sssBCTQ (r=-0.34, P=0.009) and the total NPSI score (r=-0.41, P=0.001) correlated to a more altered EMLA test grade, but not to any NCS or SSR variables. In symptomatic hands, burning sensation was associated with more severe small-fiber lesion, while other pain and sensory symptoms were rather found to be reduced in case of large-fiber damage, evidenced by NCS alteration. CONCLUSIONS This study confirms the discrepancy between conventional NCS results and clinical presentation of CTS, but still suggests a major involvement of Aβ fibers in the positive sensory symptoms of CTS, excepting burning sensation. On the other hand, the EMLA test was found to correlate with clinical data and to be able to improve sensitivity of neurophysiological investigation in diagnosing CTS.

Characterization of Neuropathic Pain in Primary Sjögren’s Syndrome with Respect to Neurophysiological Evidence of Small-Fiber Neuropathy

OBJECTIVE To determine whether clinical features of neuropathic pain differ with respect to the presence of small-fiber neuropathy (SFN) in patients with primary Sjögrens syndrome (pSS). METHODS We compared the clinical presentation of neuropathic pain between 15 patients with pSS and SFN detected by neurophysiological tests (laser-evoked potentials, cold and warm detection thresholds, sympathetic skin responses, and electrochemical skin conductance) and 15 patients with pSS but no neurophysiological evidence of SFN. RESULTS The patients with SFN had more intense squeezing and pressure sensations and more frequent dynamic mechanical allodynia (pain provoked by brushing) than the patients without SFN. Restless leg syndrome was also more frequently observed in patients with SFN, who had pain aggravated at rest that improved by moving. CONCLUSIONS These findings are in favor of the sensitization of relatively spared large Aβ-fibers and second-order nociceptive neurons in patients with SFN. On the other hand, burning sensations, which rather reveal sensitization of small nociceptive fibers, were observed whether SFN was present or not. Thus, some discriminating clinical features may help to suggest the presence of SFN in patients with pSS and chronic neuropathic pain.

How to explore automic dysfunction on clinical practice

Objectives Various validated clinical scales and questionnaires are available and many neurophysiological and functional tests have been developed to evaluate dysautonomia. This work aims to review the neurophysiological tools that can be used to characterize distal autonomic dysfunction, particularly in the context of peripheral neuropathies. Methods Neurophysiological tests exploring autonomic vasomotor and sudomotor function have been reviewed. The accuracy of each technique for the diagnosis of small-fiber autonomic neuropathy has been assessed. Results Sudomotor innervation can be investigated by many tests including sympathetic skin reflex recording (SSR), quantitative sudomotor axon reflex testing (QSART), electrochemical skin conductance measurement (ESC) by Sudoscan®, and the Neuropad® colorimetric test. Both the Neuropad® test and ESC measurement by Sudoscan®, provide early markers of neuropathy in context of familial amyloid polyneuropathy as well as in diabetic polyneuropathy. The Neuropad® test could be used as a screening tool, requiring confirmation by ESC measurement by Sudoscan®, which is more convenient for follow-up assessment. Unlike the SSR, QSART is also a sensitive test for detecting sudomotor dysfunction. However, its test-retest reliability is really moderate. For vasomotor aspects, investigation includes the stimulated skin wrinkling (SSW) test, laser Doppler flowmetry (LDF) and laser Doppler imaging (LDI-flare). The SSW test appears valuable when applied to the fingers, but not to the toes. The LDF and LDI-flare tests were found to be sensitive in various clinical contexts (e.g., Parkinsons disease, diabetes, and HIV infection), but they lack standardization and have poor test-retest reliability, especially LDF. Conclusion Sudomotor tests and notably ESC measurement by Sudoscan® appear to be relevant to assess distal autonomic dysfunction in the context of peripheral neuropathy, while the reliability of vasomotor tests should still be improved. Finally, various autonomic tests that are not performed at limb extremities can also be very informative and sensitive in this clinical context, such as heart rate variability measurement at deep breathing.

Assessment of autonomic innervation of the foot in familial amyloid polyneuropathy

Distal involvement of autonomic nerve fibers is critical in familial amyloid polyneuropathy (FAP) due to transthyretin (TTR) mutation. This study compares different methods for assessing autonomic foot innervation in TTR‐FAP patients.