Painful and painless peripheral sensory neuropathies due to HIV infection: a comparison using quantitative sensory evaluation

In order to characterize further, sensory disorders due to HIV-induced distal symmetrical polyneuropathy (DSPN), we compared quantitative sensory testing (QST) and electrodiagnostic parameters in patients presenting with painful or painless DSPN. Forty HIV patients with DSPN were studied and compared with ten seronegative control subjects: 15 patients presented with pains (spontaneous and/or evoked) in the lower limbs and 25 patients, matched for age, sex, duration of HIV and CD4 count, had non-painful symptoms (i.e. paresthesia). QST and nerve conduction studies (NCS) were performed on the lower limbs. von Frey hairs and a thermotest device were used to determine the mechanical- and thermal-, detection and pain thresholds. The responses elicited by suprathreshold thermal and mechanical stimuli were measured on a visual analog scale (VAS), to evaluate hyperalgesia. NCS were not significantly different between the two groups of patients. Thermal and mechanical detection thresholds, as well as the thermal pain threshold were significantly, and similarly, increased in both groups of patients as compared with the normal control subjects. Responses to suprathreshold thermal stimuli were similar in patients and control subjects. In contrast, mechanical pain thresholds were significantly decreased (mechanical allodynia) and responses to suprathreshold mechanical stimuli significantly increased (mechanical hyperalgesia) in the pain, but not in the painless patients. The intensity of mechanical allodynia/hyperalgesia was correlated with the intensity of spontaneous ongoing pain. We conclude that patients with DSPN are characterized by thermal, mechanical and electrophysiological deficits, suggestive of alterations in both small and large peripheral nerve fibers. Patients with a painful neuropathy present with static mechanical allodynia/hyperalgesia, suggestive of a selective alteration in the processing of mechanoreceptive signals, which might have a significant role in the pathophysiology of spontaneous and evoked pains in these patients.     

Bilateral widespread mechanical pain hypersensitivity as sign of central sensitization in patients with cluster headache

Objective.— To investigate bilateral widespread pressure pain hyperalgesia in deep tissues over symptomatic (trigemino‐cervical) and nonsymptomatic (distant pain‐free) regions in patients with cluster headache (CH). Background.— Central sensitization is claimed to play a relevant role in CH. No study has previously searched for widespread pressure hyperalgesia in deep tissues over both symptomatic (trigemino‐cervical) and nonsymptomatic (distant pain‐free) regions in patients with CH. Methods.— Sixteen men (mean age: 43 ± 11 years) with CH in a remission phase and 16 matched controls were recruited. Pressure pain thresholds (PPTs) were bilaterally measured over the supra‐orbital (V1), infra‐orbital (V2), mental (V3), median (C5), radial (C6), and ulnar (C7) nerves, C5‐C6 zygapophyseal joint, mastoid process, and tibialis anterior muscle by an assessor blinded to the subjects' condition. Results.— The results showed that PPT levels were significantly decreased bilaterally in patients with CH as compared with healthy controls (all sites, P < .001). A greater degree of sensitization over the mastoid process (P < .001) and a lower degree of sensitization over the tibialis anterior muscle (P < .01) was found. Conclusions.— Our findings revealed bilateral widespread pressure pain hypersensitivity in patients with CH confirming the presence of central sensitization mechanisms in this headache condition.     

Cluster headache with aura

The objective of our study is to report the frequency and characteristics of cluster headache with aura among the population of patients with cluster headache treated in our outpatient neurology clinic. 254 patients were submitted to semi-structured interviews to identify the presence of symptoms similar to the migraine aura. 5 patients who suffered from a cluster headache with aura filled a diary with the characteristics of the pain attacks and the aura. All the patients with either episodic or chronic cluster headache were studied. The pain attacks were associated with symptoms similar to the migraine aura in five patients (2%). These disorders were usually ipsilateral to the pain and consisted of paresthesias of the trigeminal territory, clumsiness of the limbs or visual disturbances. Neither paresis nor hypoesthesia could be proved by clinical examination during the attack. We propose to reserve the name of cluster headache with aura to these cases that show similar symptomatology to the migraine aura. These manifestations suggest the participation of the central nervous system in this type of cluster headache. Received: 16 July 2001, Accepted in revised form: 4 December 2001 Correspondence to E. Martínez-Fernández     

Heterogeneous sensory processing in persistent postherniotomy pain

Previous studies on sensory function in persistent postherniotomy pain (PPP) have only identified pressure pain threshold to be significantly different from pain-free patients despite several patients reporting cutaneous pain and wind-up phenomena. However the limited number of patients studied hinders evaluation of potential subgroups for further investigation and/or treatment allocation. Thus we used a standardized QST protocol to evaluate sensory functions in PPP and pain-free control patients, to allow individual sensory characterization of pain patients from calculated Z-values. Seventy PPP patients with pain related impairment of everyday activities were compared with normative data from 40 pain-free postherniotomy patients operated >1 year previously. Z-values showed a large variation in sensory disturbances ranging from pronounced detection hypoesthesia (Z = 6, cold) to pain hyperalgesia (Z = −8, pressure). Hyperalgesia for various modalities were found in 80% of patients, with pressure hyperalgesia in ∼65%, and cutaneous (mechanical or thermal) hyperalgesia in ∼35% of patients. The paradoxical combination of tactile hypoesthesia and hyperalgesia was seen in ∼25% of patients. Increased pain from repetitive tactile and/or brush stimulation was found in 51%, suggesting a role of altered central nociceptive function in this subpopulation. A high incidence (26%) of pressure hyperalgesia was found in the contralateral groin, with a significant correlation (rho = 0.58, p = 0.002) to the hyperalgesic level on the painful side, again suggesting central nervous mechanisms in PPP. In conclusion, this study shows that a standardized trauma results in heterogeneous combinations of hypo- and hyperalgesia. Z-score evaluation of sensory function identifies subpopulations in PPP, which may be used in selecting surgical and/or pharmacological treatment strategies.     

Corneal Sensitivity in Cluster Headache

SYNOPSIS
Cluster headache pain is thought to arise from vasodilatation, but a neural origin of the pain has never been completely excluded. Some patients with cluster headache have complained of subjective diminution of sensation over the ipsilateral forehead. This is hard to quantitate and is often variable. Besides, ablation of trigeminal sensory pathways has been re sorted to for relief of pain in some intractable cases.
The present study was undertaken to quantitatively assess the sensitivity of the cornea in cluster patients. Fifteen cluster headache patients were the subjects of this study. Measurement of the corneal sensitivity was undertaken using a Cochet-Bonnet Aesthesiometer. There was no difference between the affected and the unaffected eye. There was no difference in the sensitivity when testing was done during the cluster period and later on when the patients were in remission. It is concluded from this study that there is no objective evidence for involvement of trigeminal sensory pathways in patients with cluster headache.     

Brush allodynia in hospitalized headache patients

OBJECTIVE: To describe the incidence and time course of dynamic mechanical allodynia (brush allodynia, BA) in an inpatient headache population. BACKGROUND: Four types of cutaneous allodynia (heat, cold, static mechanical [pressure], and dynamic mechanical [brush] allodynia) can be studied in headache patients. In episodic migraineurs, the development of cutaneous allodynia heralds a change in treatment response. However, little is known about the functional significance of BA, and little is known about the frequency of any type of cutaneous allodynia among patients with chronic or more severe headache disorders. Methods.-The protocol was approved by the institutional review board of our university hospital. A total of 78 subjects were tested for allodynia on days 1, 3, and 5 of an inpatient hospital stay using a 4 x 4 folded gauze pad stroked 10 times at three bilateral sites (forehead, jaw, and forearm). Subjects were queried about the signs and symptoms of their headaches. Headache intensity was graded with a verbal 11-point scale and the intensity of allodynia was graded using a 10 cm visual analog scale. RESULTS: A total of 61 patients had transformed migraine (TM). BA was present at some point during the hospitalization in 32 subjects (41%). Neither age nor duration of daily headache correlated with headache severity. Headache intensity, a history of sensory symptoms or weakness, and subjective blurred vision accompanying the headache correlated with the presence of BA (P< or = .05). Unilateral headaches were more likely to be associated with BA (P = .01), independent of headache severity. When headache was unilateral, BA was greatest ipsilateral to the headache. BA did not influence outcome as measured by length of stay or the likelihood of being discharged headache-free. The rate of decline of headache intensity and allodynia score were similar. CONCLUSION: BA is common in hospitalized headache patients. Subjects with more severe unilateral headaches were more likely to have BA. The presence of BA did not predict treatment failure in an inpatient setting.     

Impaired circadian rhythmicity of nociceptive reflex threshold in cluster headache

BACKGROUND: Alteration of circadian rhythmicity involving several endocrinologic and autonomic parameters has been observed in cluster headache. OBJECTIVES: To explore whether circadian failure of the pain control system may exist in cluster headache. METHODS: The nociceptive flexion reflex threshold was studied in 25 patients with episodic cluster headache (14 active, 11 in remission) and 6 patients with chronic cluster headache, along with 10 normal volunteers throughout a 24-hour period. The reflex response was evoked at the level of the biceps femoris by stimulating the sural nerve at the ankle. Single and population mean cosinor methods were used to detect the circadian rhythmicity. RESULTS: In the patients with episodic cluster headache, a significant reduction in the nociceptive flexion reflex threshold was observed in both the active subgroup and the subgroup in remission (P < .05). In these patients, persistence of a significant 24-hour rhythm during both the active period and remission was observed, but a shift of the phase was observed during clinical activity when compared with the remission period. A lack of circadian nociceptive flexion reflex threshold rhythmicity was found in the patients with chronic cluster headache. CONCLUSIONS: Our findings suggest that in cluster headache there may be impairment of the pain control system that is associated with periodic failure of the mechanisms involved in the organization of biological rhythms.     

Role of Methadone in Induction and/or Exacerbation of Cluster Headache in Patients Treated for Opioid Addiction

Methadone is a potent opioid agonist widely used in opioid maintenance therapy. In some countries, methadone is available for pain treatment. We report the cases of two patients with history of substance abuse (mainly heroin), who presented with cluster headache possibly related to high-dose methadone. One possible explanation for the severe pain described in these cases is hyperalgesia induced by high doses of methadone.     

Respiratory Sinus Arrhythmia in Cluster Headache Syndrome

SYNOPSIS
Respiratory sinus arrhythmia is regarded as indicative of cardiac vagal integrity. A ratio of the longest R-R interval to the shortest R-R interval during deep breathing test (E:I ratio) was calculated in controls (n=49), cluster headache (n=33) and CPH (n=4) patients, E:I ratio decreased with age but was not dependent upon sex or upon smoking habits. Furthermore, there were no significant differences as regards E:I ratio between cluster headache patients in and outside a bout, or between patients with right-sided and left-sided headache. However, the E:I ratio was found to be significantly lower in the cluster headache group as such, when compared with controls, but the number of patients disclosing pathological or borderline results was small, 2 and 2, respectively. This may indicate that a putative vagal dysfunction in cluster headache is usually less marked than in patients with e.g. diabetic autonomic neuropathy. Significant attack-related change in the E:I ratio were detected in all individual patients though these changes were not of a uniform nature from individual to individual. E:I ratios were rather high in 3 out of 4 CPH patients examined. However, the number of patients in this group is too small to allow definite statements about the difference between CPH end cluster headache with regard to E:I ratios. There was no significant difference between E:I ratios outside and during a mild, short, mechanically precipitated attack in a single CPH patient.     

Effects of symptomatic treatments on cutaneous hyperalgesia and laser evoked potentials during migraine attack

Previously an amplitude enhancement of laser evoked potentials (LEPs) was detected during migraine attack: we further examined pain threshold to CO2 laser stimuli and LEPs during attacks, evaluating the effect of almotriptan, lysine-acetylsalicylate and placebo treatment on cutaneous hyperalgesia to thermal stimuli delivered by CO2 laser and on LEP components. Eighteen patients suffering from migraine without aura were analysed. They were divided into three groups of six patients each, randomly assigned to lysine acetyl-salicylate, almotriptan or placebo treatments. The supraorbital zones and the dorsum of the hand were stimulated on both the symptomatic and not symptomatic side in all patients. The LEPs were recorded by 25 scalp electrodes. During attacks, the P2 wave was significantly enhanced; the amplitude of the P2 component obtained by the stimulation of the supraorbital zone during the attack on the side of the headache was significantly correlated with the intensity of pain and the frequency of headache. Both almotriptan and lysine acetyl-salicylate significantly reduced the P2 amplitude but they showed no effects on hyperalgesia to laser stimulation; headache relief following therapy was correlated with the reduction of the P2 amplitude. The cortical elaboration of laser-induced experimental pain seemed increased during migraine attack, and the severity of headache was mainly related to the increase of the later LEPs components expressing the attentive and emotive compounds of suffering. Reversion of this process appeared to be primarily responsible for the efficacy of drugs in treating migraine, though both almotriptan and lysine-acetil salicilate seemed to have no effect in reducing sensitization at second and third order nociceptive neurons.     

Deep tissue afferents, but not cutaneous afferents, mediate transcutaneous electrical nerve stimulation-Induced antihyperalgesia.

In this study we investigated the involvement of cutaneous versus knee joint afferents in the antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS) by differentially blocking primary afferents with local anesthetics. Hyperalgesia was induced in rats by inflaming one knee joint with 3% kaolin-carrageenan and assessed by measuring paw withdrawal latency to heat before and 4 hours after injection. Skin surrounding the inflamed knee joint was anesthetized using an anesthetic cream (EMLA). Low (4 Hz) or high (100 Hz) frequency TENS was then applied to the anesthetized skin. In another group, 2% lidocaine gel was injected into the inflamed knee joint, and low or high frequency TENS was applied. Control experiments were done using vehicles. In control and EMLA groups, both low and high frequency TENS completely reversed hyperalgesia. However, injection of lidocaine into the knee joint prevented antihyperalgesia produced by both low and high frequency TENS. Recordings of cord dorsum potentials showed that both low and high frequency TENS at sensory intensity activates only large diameter afferent fibers. Increasing intensity to twice the motor threshold recruits Adelta afferent fibers. Furthermore, application of EMLA cream to the skin reduces the amplitude of the cord dorsum potential by 40% to 70% for both high and low frequency TENS, confirming a loss of large diameter primary afferent input after EMLA is applied to the skin. Thus, inactivation of joint afferents, but not cutaneous afferents, prevents the antihyperalgesia effects of TENS. We conclude that large diameter primary afferent fibers from deep tissue are required and that activation of cutaneous afferents is not sufficient for TENS-induced antihyperalgesia. PERSPECTIVE: Transcutaneous electrical nerve stimulation (TENS) is an accepted clinical modality used for pain relief. It is generally believed that TENS analgesia is caused mainly by cutaneous afferent activation. In this study by differentially blocking cutaneous and deep tissue primary afferents, we show that the activation of large diameter primary afferents from deep somatic tissues, and not cutaneous afferents, are pivotal in causing TENS analgesia.     

Capsaicin evoked pain and allodynia in post-herpetic neuralgia

The hypothesis that the pain and allodynia associated with post-herpetic neuralgia (PHN) is maintained by a combination of input from preserved primary afferent nociceptors and sensitization of central pain transmitting neurons was examined in 17 subjects with PHN. Pain, allodynia, thermal sensory function, cutaneous innervation, and response to controlled application of 0.075% capsaicin were measured. Compared to mirror-image skin, applying capsaicin on a 9 cm(2) area of PHN skin significantly increased overall PHN pain and allodynia in 11 of 17 subjects. These 'capsaicin responders' were characterized by higher average daily pain, higher allodynia ratings, and relatively preserved sensory function at baseline compared to the non-responders. In three of the 'capsaicin responders' the area of allodynia expanded into previously non-allodynic and non-painful skin that had normal sensory function and cutaneous innervation. These observations support the hypothesis that allodynia in some PHN patients is a form of chronic secondary hyperalgesia maintained by input from intact and possibly 'irritable' primary afferent nociceptors to a sensitized CNS.     

Myocardial infarction without pain. A study of the sensory function of the upper limbs

The sensory function of the upper limbs was examined in 18 subjects who had a myocardial infarction without a well-defined episode of chest pain.The cutaneous pain threshold was significantly higher than in normals. The ischaemia of the upper limbs induced patterns of sensations different from the normals, with onset of pain and of autonomie and coenaesthesic disturbances.These modifications of the sensory function are the same as observed in subjects with a previous painful infarction, but are quite different from those observed in patients with angina pectoris.     

Quantitative sensory testing in cluster headache: increased sensory thresholds

To determine if recently reported changes in sensory thresholds during migraine attacks can also be seen in cluster headache (CH), we performed quantitative sensory testing (QST) in 10 healthy subjects and in 16 patients with CH. Eight of the patients had an episodic CH and the other eight a chronic CH. The tests were performed on the right and left cheeks and on the right and left side of the back of the hands to determine the subjects' perception and pain thresholds for thermal (use of a thermode) and mechanical (vibration, pressure pain thresholds, pin prick, von Frey hairs) stimuli. Six patients were examined in the attack-free period. Three were also willing to repeat the tests a second time during an acute headache attack, which was elicited with nitroglycerin. The healthy subjects performed the experiments in the morning and evening of the same day to determine if sensory thresholds are independent of the time of day. If they were, this would allow estimation of the influence of the endogenous cortisone concentration on these thresholds. The control group showed no influence of the time of day on the thresholds. There was a significant difference in pain sensitivity between the back of the hands and the cheeks (P<0.05): higher thresholds were found on the back of the hands. The thresholds generally exhibited little intersubject variability, indicating that QST is a reliable method. There was also a significant difference between the test areas in the patient group (P<0.001): the cheeks were also more sensitive than the back of the hands. In comparison with reference data of healthy volunteers, the detection thresholds were increased in the patients on both test areas. These were statistically significant for warmth, thermal sensory limen (TSL), heat and pressure on the back of the hands (P<0.04) and for the warmth and TSL thresholds on the cheeks (P<0.05). There were no differences in the thresholds regardless of whether the patients were examined in or outside of a cluster bout. Furthermore, we found no cutaneous allodynia in the three patients tested during an attack. The increased sensory thresholds on the cheeks as well as on the back of the hands are in agreement with an increased activation of the patients' antinociceptive system. The seasonal variation and the temporal regularity of single attacks as well as the findings in imaging studies indicate that the hypothalamus is involved in the pathophysiology of CH. In view of the strong connectivity between the hypothalamus and areas involved in the antinociceptive system in the brainstem, we hypothesize that this connection is the reason for the increased sensory thresholds in CH patients found in our study.     

Dynamic mechanical (brush) allodynia in cluster headache

OBJECTIVE: To examine the occurrence of dynamic mechanical (brush) allodynia (BA) in patients with cluster headache (CH). BACKGROUND: Cutaneous allodynia was described in migraine. It was related to sensitization of neurons in the trigeminal nucleus caudalis (TNC). This phenomenon has not been previously described in cluster headache. METHODS: We examined adult patients with episodic or chronic CH for the presence of BA. Demographic data and the characteristics of CH were obtained through a questionnaire. Allodynia testing was performed by repetitively applying a 4x4-inch gauze pad to skin areas in the trigeminal and cervical dermatomes. Degree of allodynia was measured on a 100-mm visual analog scale (VAS). The relations between the location and severity of headache and allodynia were assessed. RESULTS: Ten patients (all male, mean age 39.3) were included in the study. Seven had episodic CH (ECH) and 3 had chronic CH (CCH). Two patients were in acute attack when tested for BA. In total, 4 (40%) of the 10 patients had BA (2 [28.6%] of the 7 with ECH and 2 [66.7%] of the 3 with CCH). Median disease duration was 22 years for patients with BA and 12 years for patients without BA. Of the two patients in acute attack, one had BA, ipsilateral to the headache, which was reduced 20 minutes after treatment, along with reduced headache severity. CONCLUSIONS: This is the first report on the occurrence of cutaneous allodynia in CH. The presence of BA in CH may be related to CH type (episodic vs. chronic) and to the duration of disease. These results support the concept that allodynia in CH may result from a time-dependent process of neuronal sensitization.     

A Case‐Control Study on Cortical Thickness in Episodic Cluster Headache

Objective.— This study aims at investigating cortical thickness in cluster headache patients as compared with a healthy control group. Background.— The pathobiology of cluster headache is not yet fully understood, although a dysfunction of the hypothalamus has been suggested to be causal. Previous studies in migraine and trigeminal neuropathic pain have demonstrated changes in cortical thickness using cortex segmentation techniques, but no data have been published on cluster headache. Methods.— We investigated 12 men with episodic cluster headache during a phase without acute headache as well as age and sex‐matched healthy controls using high resolution T1‐weighted magnetic resonance imaging acquired at 3T and performed a categorical whole‐brain surface‐based comparison of cortical thickness between groups. Furthermore, a correlation analysis of disease duration and cortical thickness was conducted. Results.— In comparison with control subjects, we found a reduction of cortical thickness in the angular gyrus and the precentral gyrus in cluster headache patients contralaterally to the headache side. These reductions did not correlate with disease duration. The cortical thickness of an area within the primary sensory cortex correlated with disease duration. Conclusions.— This study demonstrates alterations in cortical thickness in cluster headache patients suggesting a potential role of cortical structures in cluster headache pathogenesis. However, it cannot be determined from this study whether the changes are cause or consequence of the disorder. The correlation of cortical thickness with disease duration in the somatosensory cortex may suggest disease‐related plasticity in the somatosensory system.     

Deep brain stimulation for intractable chronic cluster headache: proposals for patient selection

Cluster headache is the most severe of the primary headaches. Positron emission tomography and functional MRI studies have shown that the ipsilateral posterior hypothalamus is activated during cluster headache attacks and is structurally asymmetric in these patients. These changes are highly specific for the condition and suggest that the cluster headache generator may be located in that brain area; they further suggest that electrical stimulation of that region might produce clinical improvement in chronic cluster headache sufferers refractory to medical therapy. In five patients with severe intractable chronic cluster headache, hypothalamic electrical stimulation produced complete and long-term pain relief with no relevant side-effects. We therefore consider it essential to propose criteria for selecting chronic cluster headache patients for hypothalamic deep brain stimulation before this procedure is undertaken at other academic medical centres.     

Recurrent Spontaneous Paresthesia in the Upper Limb Could Be Due to Migraine: A Case Series

Transient neurologic dysfunction is a characteristic feature of migraine. About 20% of migraineurs may experience various symptoms in the absence of any headache at one time or another. Visual auras are the most common auras of migraine, and migraine is considered as the most common cause of transient vision loss in young patients. Sensory auras are the second most common migrainous auras. However, the literature is silent for isolated sensory aura as a migraine equivalent. Herein we report 14 patients with recurrent episodic paresthesia in the limbs and other body parts. All patients fulfilled the diagnostic criteria of “typical aura without headache” of ICHD‐3β. All patients were subjected to various investigations to rule out secondary causes. Ten patients received antimigraine drugs and all showed a positive response to therapy. Recurrent spontaneous paresthesia is quite common in the general population and many patients remain undiagnosed. We speculate that a subset of patients might be related to migrainous sensory auras.     

Chronic paroxysmal hemicrania: From the index patient to the disease

The first patient with chronic paroxysmal hemicrania (CPH), a 41-year-old woman, first seen in 1961, was followed until an adequate treatment was found, 12 years later. Clinically, attack frequency and duration differed widely from the general pattern of cluster headache. Ocular variables, such as intraocular pressure and corneal indentation pulse amplitudes, also differed in our case (clear symptomatic side increment during attacks) and cluster headache. Pupil reactions to directly and indirectly acting sympathicomimetic drugs were also vastly different in our case and cluster headache: no signs of Horner’s syndrome in our patient, while cluster headache exhibits a "Horner-like pattern." In cluster headache, there is a relative hypohidrosis in the forehead on the symptomatic side if body temperature is increased, and a clear hyperhidrosis on direct parasympathomimetic stimulation. This was not so in our case. Indomethacin was highly effective in our case, while "cluster headache drugs," such as ergotamine/sumatriptan, were ineffective. Indomethacin was inactive in cluster headache. Accordingly, our case seemed to differ decisively from cluster headache: CPH had been discovered.