Dysfunction of small myelinated afferents in diabetic polyneuropathy, as assessed by laser evoked potentials.

OBJECTIVE: To verify whether laser evoked potentials are useful in assessing the function of small afferent fibers and to compare dysfunction of large and small afferent fibers in patients with diabetic polyneuropathy. METHODS: The brain potentials evoked by CO2 laser stimulation of the hand and foot were studied in diabetic patients (n = 45) with various degrees of peripheral nerve damage. Laser evoked potentials (which assess the function of small myelinated afferents) were also compared with ulnar and sural nerve sensory action potentials (which assess the function of large myelinated afferents) by scoring the abnormalities of the two neurophysiological tests with similar criteria. RESULTS: Laser evoked potentials were often absent; the mean latency was normal and mean amplitude decreased, as expected in axonopathies. Although clinical examination showed more frequent impairment of vibratory than pinprick sensation, laser evoked potentials and sensory action potentials yielded similar abnormality scores and showed a strong intra-individual correlation. CONCLUSIONS: Laser evoked potentials, possibly better than standard clinical examination for assessing the abnormalities of small-diameter afferents, indicate that diabetic polyneuropathy induces large- and small-afferent dysfunction in parallel.     

Trigeminal sensory pathway function in patients with SUNCT.

OBJECTIVE: Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is a rare primary headache whose origins are unclear. To seek information on its pathophysiology, we studied the trigeminal Abeta and Adelta pathways by recording trigeminal reflexes and laser evoked potentials (LEPs) in patients with SUNCT. METHODS: Trigeminal reflexes and LEPs were recorded in 11 consecutive patients. Ten patients had neuroimaging evidence documenting idiopathic SUNCT and one had a posterior fossa tumour that compressed the trigeminal nerve thus causing symptomatic SUNCT. RESULTS: Whereas the patients with idiopathic SUNCT had normal trigeminal reflex and LEP responses, the patient with symptomatic SUNCT had abnormal responses. CONCLUSIONS: Our neurophysiological findings show that idiopathic SUNCT spares the trigeminal sensory pathways whereas symptomatic SUNCT does not. SIGNIFICANCE: Neurophysiological testing can easily differentiate the idiopathic and symptomatic forms of SUNCT. It also suggests that the two forms are pathophysiologically distinct entities.     

Sensory involvement in spinal-bulbar muscular atrophy (Kennedy's disease)

Spinal-bulbar muscular atrophy (SBMA) is a rare X-linked neuronopathy associated with an abnormal representation of androgen receptors in the nervous system. Standard nerve conduction and histopathological studies have disclosed the involvement of large myelinated sensory fibers in the spinal nerves of SBMA patients. Little is known about the involvement of small sensory neurons and trigeminal nerves. Laser evoked potentials (LEPs) were studied in 6 unrelated patients with SBMA; 5 of these patients also underwent trigeminal reflex recordings, and 3 a sural nerve biopsy. LEPs were markedly abnormal, indicating a dysfunction in pain pathways. Given the sparing of small fibers in the sural nerve specimens, we hypothesize a dysfunction in spinothalamic cells, possibly due to an abnormal representation of the androgen receptors. Except for the jaw-jerk, all the trigeminal reflexes were markedly abnormal. Since the afferents for the jaw-jerk have their cell body within the central nervous system instead of the ganglion, the selective sparing of the jaw-jerk indicates a trigeminal ganglionopathy.     

Mandibular nerve involvement in diabetic polyneuropathy and chronic inflammatory demyelinating polyneuropathy

Sensory complaints in the area of the mandible and mouth often escape notice or remain undiagnosed. Using electromyographic recording of the trigeminal reflexes and motor responses, we sought trigeminal dysfunction in 50 patients with peripheral neuropathy, and tried to gain pathophysiological information on the mechanisms provoking trigeminal damage. Trigeminal reflex recordings (early and late blink reflex after supraorbital stimulation, early and late masseter inhibitory reflex after mental stimulation, and jaw jerk) disclosed abnormalities caused by sensory trigeminal neuropathy in 8 out of 15 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 13 out of 23 patients with severe diabetic polyneuropathy, and in none of 12 patients with mild diabetic polyneuropathy. Six patients had abnormal motor responses in facial or masseter muscles. The response affected most frequently was the masseter early inhibitory reflex (also called first silent period, SP1) after mental nerve stimulation, its latency being strongly delayed. We found these long delays not only in patients with CIDP, but also in diabetic patients with severe polyneuropathy. We conclude that peripheral polyneuropathies often cause subclinical damage to the trigeminal nerve, especially to its mandibular branch. We believe that the nerve fibers running along the alveolar–mandibular pathway are more exposed to damage because of their cramped anatomical route in the mandibular canal and below the internal pterygoid muscle and fascia. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1673–1679, 1998     

Further evidence for a central reorganisation of synaptic connectivity in patients with hypoglossal-facial anastomosis in man

In normal subjects, electrical stimulation of trigeminal mucosal afferents (lingual nerve - V3) can elicit a short latency (12.5+/-0. 3 ms; mean+/-S.D.) reflex response in the ipsilateral genioglossus muscle (Maisonobe et al., Reflexes elicited from cutaneous and mucosal trigeminal afferents in normal human subjects. Brain Res. 1998;810:220-228). In the present study on patients with hypoglossal-facial (XII-VII) nerve anastomoses, we were able to record similar R1-type blink reflex responses in the orbicularis oculi muscles, following stimulation of either supraorbital nerve (V1) or lingual nerve (V3) afferents. However, these responses were not present in normal control subjects. Voluntary swallowing movements produced clear-cut facilitations of the R1 blink reflex response elicited by stimulation of V1 afferents. In a conditioning-test procedure with a variable inter-stimulus interval, the R1 blink reflex response elicited by supraorbital nerve stimulation was facilitated by an ipsilateral mucosal conditioning stimulus in the V3 region. This facilitatory effect was maximal when the two stimuli (conditioning and test) were applied simultaneously. This effect was not observed on the R1 component of the blink reflex in the normal control subjects. These data strongly suggest that in patients with XII-VII anastomoses, but not in normal subjects, both cutaneous (V1) and mucosal (V3) trigeminal afferents project onto the same interneurones in the trigeminal principal sensory nucleus. This clearly supports the idea that peripheral manipulation of the VIIth and the XIIth nerves induces a plastic change within this nucleus.     

Idiopathic and symptomatic trigeminal pain.

The trigeminal reflexes (corneal reflex, blink reflex, masseter inhibitory periods, jaw-jerk) and far field scalp potentials (nerve, root, brainstem, subcortical) evoked by percutaneous infraorbital stimulation were recorded in 30 patients with "idiopathic" trigeminal neuralgia (ITN) and 20 with "symptomatic" trigeminal pain (STP): seven postherpetic neuralgia, five multiple sclerosis, four tumour, two vascular malformation, one Tolosa-Hunt syndrome, and one traumatic fracture. All the patients with STP and two of those with ITN had trigeminal reflex abnormalities; 80% of patients with STP and 30% of those with ITN had evoked potential abnormalities. The results indicate that 1) trigeminal reflexes and evoked potentials are both useful in the examination of patients with trigeminal pain, and in cases secondary to specific pathologies provide 100% sensitivity; 2) in "symptomatic" and "idiopathic" paroxysmal pain the primary lesion affects the afferent fibres in the proximal portion of the root or the intrinsic portion in the pons; 3) primary sensory neurons of the A-beta fibre group are involved in both paroxysmal and constant pain, but in the latter the damage is far more severe.     

Electrically evoked nociceptive potentials for early detection of diabetic small‐fiber neuropathy

Background and purpose: This study investigated the utility of pain‐related evoked potentials (PREP’s) elicited by a nociceptive electrical stimulation of the skin (= electrically evoked nociceptive potentials) in early detection of diabetic small‐fiber neuropathy. Methods: We studied 36 ‘young’ (19–35 years) and 24 ‘older’ (36–65 years) healthy subjects as well as 35 patients (35–64 years) with diabetes and neuropathic symptoms and 22 patients (34–64 years) with diabetes without neuropathic symptoms. Only patients with normal standard nerve conduction testing were included. Results: In patients with neuropathic symptoms, we found a significant increase in PREP latencies and decrease of amplitudes elicited from both, upper and lower limbs. In non‐symptomatic diabetic patients, we observed PREP abnormalities from lower limbs only. Conclusions: These data suggest that the method of pain‐related evoked potentials elicited by a nociceptive electrical stimulation of the skin may contribute to the early detection of diabetic sensory neuropathy.     

Clinical application of laser evoked potentials using the Nd:YAG laser.

The clinical interest of a new type of laser evoked potentials (LEPs) using Nd:YAG laser was assessed in the diagnosis of peripheral neuropathies affecting the small-diameter nerve fibres, and of spinal cord lesions, affecting the spinothalamic tract. Twelve patients aged from 26 to 79 years with sensory neuropathies (n = 6) or spinal cord lesions (n = 6) underwent neurophysiological examination of the lower limbs comprising quantitative sensory testing, i.e., the determination of vibratory and thermal thresholds (VT and TT), somatosensory evoked potentials (SEPs) to electrical stimulation and Nd:YAG LEPs. VT and SEPs were used to assess large-diameter afferent nerve fibres and the lemniscal pathways while TT and LEPs were used to assess small-diameter afferent nerve fibres and the spinothalamic tract. In addition, patients with peripheral neuropathy underwent also standard nerve conduction studies to explore large fibres and the recording of sympathetic skin responses (SSRs) to explore small fibres, whereas motor evoked potentials were performed in patients with spinal cord lesion. LEPs were absent bilaterally in all patients with polyneuropathy, even when TT remained within the normal limits and SSRs were present. LEPs were absent after stimulation of the affected limb in all patients with a spinal cord lesion, and allowed to detect subclinical contralateral lesion in two cases. LEPs following Nd:YAG laser stimulation are sensitive in the diagnosis of peripheral and/or central nervous system disorders and they give complementary information as compared to routine electrophysiological tests.     

Trigeminal sensory input elicited by electric or magnetic stimulation interferes with the central motor drive to the intrinsic hand muscles.

In 6 normal subjects, unilateral supraorbital magnetic or electric stimulation resulted in a consistent symmetrical inhibition of the motor evoked potentials (MEPs) of the relaxed and preactivated first dorsal interosseus (FDI) muscle. A supraorbital stimulus caused a significant reduction in amplitude when the trigeminal CS was given 30 to 65 ms before transcranial magnetic stimulation (TMS). In addition, supraorbital magnetic stimulation induced a bilateral EMG suppression of the isometrically contracting FDI muscles, starting about 40 to 50 ms after the magnetic stimulus. In 4 subjects, MEPs evoked by transcranial electric stimulation or by TMS during slight muscle contraction showed a comparable trigeminomotor inhibition. These findings demonstrate that electromagnetic stimulation of trigeminal afferents interferes with the motor output to the intrinsic hand muscles inducing a bilateral inhibition which is probably mediated by a multisynaptic subcortical network. In all 6 subjects, TMS over the motor hand area or the cerebellum elicited a reproducible blink reflex. Since the blink reflex is a sensitive indicator of trigeminal excitation, one has to assume that TMS is associated with a significant excitation of trigeminal afferents. Therefore, trigeminomotor inhibition has to be considered in all TMS studies that use a conditioning-test design.     

Assessment of trigeminal small-fiber function: brain and reflex responses evoked by CO2-laser stimulation

Laser pulses selectively excite mechano-thermal nociceptors and evoke brain potentials that may reveal small-fiber dysfunction. We applied CO2-laser pulses to the perioral and supraorbital regions and recorded the scalp laser-evoked potentials (LEPs) and reflex responses in the orbicularis oculi, masticatory, and neck muscles in 30 controls and 10 patients with facial sensory disturbances. Low-intensity pulses readily evoked scalp potentials consisting of a negative component with a latency of 165 ms followed by a positive component at 250 ms. In vertex recordings, the amplitude of LEPs exceeded 30 microV. Although only high-intensity pulses evoked reflex responses, some subjects showed--even to low-intensity pulses--an orbicularis oculi (blink-like) response that markedly contaminated the scalp recording. Scalp LEPs were abnormal in patients with hypalgesia and normal trigeminal reflexes and normal in patients with normal pain sensitivity and abnormal trigeminal reflexes. Possibly because of the high receptor density in this area and the short conduction distance, laser stimulation of the trigeminal territory yields low-threshold and large LEPs, which are useful for detecting dysfunction in peripheral and central pain pathways.     

Small-fiber dysfunction in trigeminal neuralgia: carbamazepine effect on laser-evoked potentials.

BACKGROUND: In patients with trigeminal neuralgia, results of clinical examination of sensory function are normal. Reflex and evoked potential studies have already provided information on large-afferent (non-nociceptive) function. Using laser-evoked potentials (LEP), the authors sought information on small-afferent (nociceptive) function. METHODS: The brain potentials evoked by CO(2)-laser pulses directed to the perioral and supraorbital regions were studied in 67 patients with idiopathic or symptomatic trigeminal neuralgia and 30 normal subjects. Of the 67 patients, 49 were receiving carbamazepine. RESULTS: All patients with symptomatic and 51% of those with idiopathic trigeminal neuralgia had frankly abnormal LEP on the painful side. The mean latency was significantly higher and mean amplitude lower on the painful than the nonpainful side. However, even on the nonpainful side, the mean latency was significantly longer than that of the age-matched controls. The nonpainful-side latency correlated significantly with the carbamazepine dose. CONCLUSIONS: LEP detect severe impairment of the nociceptive afferent system on the painful side of patients with idiopathic as well as symptomatic trigeminal neuralgia. A dysfunction of small-myelinated afferents may play an important role in the pathophysiology of neuralgic pain. Carbamazepine markedly dampens these brain potentials. The authors propose that this effect may result from inhibition of nociceptive transmission in the cingulate gyrus.     

Corneal reflex in normal and pathological subjects

The orbicularis oculi response can be evoked both by mechanical stimulation of the cornea (corneal reflex) and by electrical stimulation of the skin overlying the supraorbital nerve (blink reflex). Mechanical stimuli to the cornea activate A delta and C free nerve endings of the corneal mucosa. Electrical stimuli to the supraorbital nerve activate A beta, A delta and C fibers of the nerve trunk. Both reflexes present a bilateral late response, but the blink reflex shows in addition an early ipsilateral component (R1), which has never been observed with the corneal stimulation in man. We have developed a simple technique of electrical stimulation of the cornea which provides stable responses and allows precise measurements of threshold and latency of the reflex. In normal subjects, the threshold ranged from 50 to 350 microA, and the maximal stimulus that the subject could bear (tolerance level) ranged from 1000 to 2500 microA. The minimal latency to tolerance level stimuli was 39 +/- 3 msec. The latency difference between the direct responses evoked from the two opposite corneas never exceeded 8 msec and the difference between the direct and consensual responses elicited from the same cornea never exceeded 5 msec. An early ipsilateral component similar to the R1 response of the blink reflex was not observed, even with supramaximal stimulation. The electrically evoked corneal reflex was normal in 10 cases of essential trigeminal neuralgia, while the responses showed significant abnormalities in 18 subjects submitted to thermocoagulation of the Gasserian ganglion as a treatment of neuralgic pain, as well as in 2 cases of symptomatic neuralgia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blink reflex alterations in diabetic patients with or without polyneuropathy

The main aim of this study is to evaluate the role of blink reflex for early diagnosis of cranial neuropathy in diabetic patients with or without polyneuropathy. Ninety-five diabetic patients were included in the present study for the evaluation of blink reflex. The diabetic patients were divided into two groups according to having diabetic neuropathy or not. Both R1, R2i and R2c latencies in all diabetic patients with or without polyneuropathy were prolonged relative to controls and the differences were statistically significant (p < .001). R1 latencies in diabetic patients with polyneuropathy were prolonged relative to diabetic patients without polyneuropathy and the differences were statistically significant (p < .001). These findings presumably reflect that facial nerve is severly involved in diabetic polyneuropathy. Finally blink reflex is of value in detection of clinically silent intraaxial brainstem functional abnormalities or extraaxial lesions in diabetic patients before peripheral neuropathy.     

Corneal reflex latency in trigeminal nerve lesions

Using a new technique to record the latency of the corneal reflex, we established normal values in 32 normal subjects between 10 and 80 years of age, divided into three age groups. In 15 patients with unilateral trigeminal nerve lesions, comparison of the responses on both sides permitted differentiation of afferent and efferent lesions.     

Electrophysiological studies in cerebrotendinous xanthomatosis.

Seven patients with cerebrotendinous xanthomatosis (CTX) were studied by electrophysiological techniques. The percentages of abnormalities detected in nerve conduction studies and electroencephalograms were 28.6% (two patients) and 100%, respectively. All patients showed prolonged central conduction times in short latency somatosensory evoked potentials (SSEPs) by tibial nerve stimulation but normal SSEPs by median nerve stimulation. Brain stem auditory evoked potentials and visual evoked potentials were abnormal in three (42.9%) and four patients (57.1%), respectively. These electrophysiological parameters were correlated with the ratio of serum cholestanol to cholesterol concentration. The results of SSEPs suggest that the polyneuropathy in CTX is caused by distal axonopathy affecting longer axons before shorter axons (central-peripheral distal axonopathy).     

On the cause of hyporeflexia in the Holmes-Adie syndrome

Electrophysiologic studies were carried out on 11 patients with Holmes-Adie syndrome, 8 of whom had reduced or absent ankle jerks. Conduction velocities and evoked nerve and muscle compound action potentials in the peroneal, posterior tibial, and sural nerves were normal. The H reflex was absent (or virtually absent) in the patients with depressed reflexes. The amplitude of the composite Ia EPSP in single soleus motoneurons was estimated from changes in firing probability of voluntarily activated soleus motor units in response to stimulation of low threshold afferents in the tibial nerve. These amplitudes were used to test the afferent side of the reflex pathway. Composite group Ia EPSPs in Holmes-Aide patients with hyporeflexia were smaller than normal or absent, indicating that the areflexia in the Holmes-Aide syndrome is due to loss of large spindle afferents or reduced effectiveness of their monosynaptic connections to motoneurons.     

Abnormalities in sensory and mixed evoked potentials in ataxia-telangiectasia.

Electromography, motor, sensory and mixed nerve conduction velocity, and H reflex were studied in four patients with ataxia-telangiectasia. The earliest and most striking electrophysiologial finding was the reduced amplitude of evoked nerve potentials. In the oldest patient, findings suggestive of spinal atrophy and mild reduction of the motor and sensory nerve conduction velocities were found. Reduced amplitude in the evoked nerve potentials can be observed without clinical evidence of peripheral neuropathy. Electrophysiological abnormalities are more severe in older than in young patients. Sural nerve biopsy in one patient showed mild changes: loss of the largest myelinated fibres and demyelination of some fibres. The ratio between maximum conduction velocity of the sural nerve and the diameter of the largest fibres was in the lower limits of the normal range. The resemblance between electrophysiological abnormalities in Friedreich's ataxia and ataxia-telangiectasia is discussed.     

F-responses of human facial muscles. A single motoneurone study

Late responses to percutaneous electrical stimulation of the facial nerve of normal man were studied in single facial motoneurones by means of single fibre EMG recordings. On the basis of latency variation and the relationship to direct responses, late responses could be differentiated in 4 types: reflex responses with small and large latency variation respectively; axon reflexes due to branching of the motor axons, and recurrent responses following antidromic activation of the motor axons.The reflex responses were due to stimulation of neighbouring trigeminal afferents and corresponded to the first and second component of the blink reflex. Axon reflexes indicate that branching of the axons may occur even in the intracranial and perhaps in the intracerebral course of the nerve. Recurrent responses exhibited very small variations in latency; they could be facilitated by subthreshold depolarization of the soma-dendritic membrane.     

Dissociation between cutaneous silent period and laser evoked potentials in assessing neuropathic pain

In this study we investigate whether the cutaneous silent period (CSP)—an inhibitory response evoked in hand muscles by painful digital nerve stimulation—is useful for assessing nociceptive pathway function in patients with neuropathic pain. In 40 patients with peripheral neuropathy (21 without and 19 with neuropathic pain) we recorded the CSP in the abductor digiti minimi after fifth digit stimulation and also recorded laser evoked potentials (LEPs) after stimulation applied to the ulnar territory of the hand. Although the LEP amplitude was significantly lower in patients with pain than in those without (P < 0.005), the CSP duration did not differ between groups (P > 0.50). Pain intensity correlated significantly with LEP amplitudes (P < 0.005) but not with CSP duration (P > 0.5). Our findings indicate that the CSP is not useful for assessing nociceptive pathway function in patients with neuropathic pain. Muscle Nerve, 2008     

Analysis of reflex activity in cardiac sympathetic nerve induced by myelinated phrenic nerve afferents

Electrical stimulation of the phrenic nerve afferents evoked excitatory responses in the right inferior cardiac sympathetic nerve in chloralose-anaesthetized cats. The reflex was recorded in intact and spinal cats. The latency and threshold of the volley recorded from the phrenic nerve as well as of the cord dorsum potentials evoked by electrical stimulation of the phrenic nerve indicated that group III afferents were responsible for this reflex. The phrenicocardiac sympathetic reflex recorded in intact cats was followed by a silent period. The maximum amplitude of the reflex discharges was 800 microV, the latency was 83 ms and the central transmission time 53 ms. Duration of the silent period lasted up to 0.83 s. In spinal cats the reflex was recorded 5.5-8 h after spinalization. The maximum amplitude of the spinal reflex discharges ranged from 22 to 91 microV and the latency from 36 to 66 ms.