CNS Measures of Pain Responses Pre- and Post-Anesthetic Ketamine in a Patient with Complex Regional Pain Syndrome.

BACKGROUND: Previous reports have indicated that ketamine anesthesia may produce significant improvement if not complete recovery of patients with complex regional pain syndrome (CRPS). AIMS: Here we report on a patient who had CRPS affecting mainly the right side of her body who underwent functional magnetic resonance imaging (fMRI) scans prior to and in the months following apparent successful treatment with anesthetic doses of ketamine. MATERIALS AND METHODS: The patient underwent two imaging sessions: one during her pain state (CRPS+) and 1 month after her ketamine treatment in her pain-free state (CRPS-). Both spontaneous and evoked (brush, cold, and heat) pain scores decreased from 7­9/10 on a visual analog scale prior to the treatment to 0­1 immediately following and for months after the treatment. For each imaging session, the identical mechanical (brush) and thermal (cold and heat) stimuli were applied to the same location (the skin of the dorsum of the right hand). RESULTS: Comparison of CRPS+ vs CRPS- for the three stimuli showed significant changes throughout the cerebral cortex (frontal, parietal, temporal, cingulate, and hippocampus), in subcortical regions such as caudate nucleus, and in the cerebellum. In addition, resting state network analysis showed a reversal of brain network state, and the recovered state paralleled specific default networks in healthy volunteers. DISCUSSION: The observed changes in brain response to evoked stimuli provide a readout for the subjective response. CONCLUSION: Future studies of brain function in these patients may provide novel insight into brain plasticity in response to this treatment for chronic pain.

Elevated blood levels of inflammatory monocytes (CD14+ CD16+ ) in patients with complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a chronic pain disorder. Although its pathophysiology is not completely understood, neurogenic inflammation is thought to play a significant role. Microglia and astrocytes are activated following tissue injury or inflammation and have been reported to be both necessary and sufficient for enhanced nociception. Blood-borne monocytes/macrophages can infiltrate the central nervous system (CNS) and differentiate into microglia resulting in hypersensitivity and chronic pain. The primary aim of this study was to evaluate the proportion of the proinflammatory CD14(+) CD16(+) monocytes as well as plasma cytokine levels in blood from CRPS patients compared to age- and gender-matched healthy control individuals. Forty-six subjects (25 CRPS, 21 controls) were recruited for this study. The percentage of monocytes, T, B or natural killer (NK) cells did not differ between CRPS and controls. However, the percentage of the CD14(+) CD16(+) monocyte/macrophage subgroup was elevated significantly (P<0·01) in CRPS compared to controls. Individuals with high percentage of CD14(+) CD16(+) demonstrated significantly lower (P<0·05) plasma levels on the anti-inflammatory cytokine interleukin (IL)-10. Our data cannot determine whether CD14(+) CD16(+) monocytes became elevated prior to or after developing CRPS. In either case, the elevation of blood proinflammatoty monocytes prior to the initiating event may predispose individuals for developing the syndrome whereas the elevation of blood proinflammatory monocytes following the development of CRPS may be relevant for its maintenance. Further evaluation of the role the immune system plays in the pathogenesis of CRPS may aid in elucidating disease mechanisms as well as the development of novel therapies for its treatment.

Migraine may be a risk factor for the development of complex regional pain syndrome.

The aim was to assess the relative frequency of migraine and the headache characteristics of complex regional pain syndrome (CRPS) sufferers. CRPS and migraine are chronic, often disabling pain syndromes. Recent studies suggest that headache is associated with the development of CRPS. Consecutive adults fulfilling International Association for the Study of Pain criteria for CRPS at a pain clinic were included. Demographics, medical history, and pain characteristics were obtained. Headache diagnoses were made using International Classification of Headache Disorders, 2nd edn criteria. Migraine and pain characteristics were compared in those with migraine with those without. anova with Tukey post hoc tests was used to determine the significance of continuous variables and Fisher's exact or χ(2) tests for categorical variables. The expected prevalence of migraine and chronic daily headache (CDH) was calculated based on age- and gender-stratified general population estimates. Standardized morbidity ratios (SMR) were calculated by dividing the observed prevalence of migraine by the expected prevalence from the general population. The sample consisted of 124 CRPS participants. The mean age was 45.5 ± 12.0 years. Age- and gender-adjusted SMRs showed that those with CRPS were 3.6 times more likely to have migraine and nearly twice as likely to have CDH as the general population. Aura was reported in 59.7% (74/124) of participants. Of those CRPS sufferers with migraine, 61.2% (41/67) reported the onset of severe headaches before the onset of CRPS symptoms Mean age of onset of CRPS was earlier in those with migraine (34.9 ± 11.1 years) and CDH (32.5 ± 13.4 years) compared with those with no headaches (46.8 ± 14.9 years) and those with tension-type headache (TTH) (39.9 ± 9.9 years), P < 0.05. More extremities were affected by CRPS in participants with migraine (median of four extremities) compared with the combined group of those CRPS sufferers with no headaches or TTH (median 2.0 extremities), P < 0.05. The presence of static, dynamic and deep joint mechano-allodynia together was reported by more CRPS participants with migraine (72.2%) than those with no headaches or TTH (46.2%), P ≤ 0.05. Migraine may be a risk factor for CRPS and the presence of migraine may be associated with a more severe form of CRPS. Specifically: (i) migraine occurs in a greater percentage of CRPS sufferers than expected in the general population; (ii) the onset of CRPS is reported earlier in those with migraine than in those without; and (iii) CRPS symptoms are present in more extremities in those CRPS sufferers with migraine compared with those without. In addition, as we also found that the presence of aura is reported in a higher percentage of those CRPS sufferers with migraine than reported in migraineurs in the general population, further evaluation of the cardiovascular risk profile of CRPS sufferers is warranted.

Quantitative autoradiographic maps of local cerebral glucose metabolism in awake rats: I. Septal region and anterior hypothalamus.

Quantitative 14C-2-deoxyglucose autoradiography was used to determine the local cerebral glucose metabolic rate (lCMRG) of nuclei in the septal region and anterior hypothalamus of awake, unanesthetized rats. The lCMRG of the medial and lateral septal areas, preoptic areas, medial preoptic nuclei, suprachiasmatic nuclei, supraoptic nuclei, anterior hypothalamic nuclei, and paraventricular nuclei were measured. The lCMRG of each nucleus was mapped at successive rostral-caudal levels to determine significant internuclear and intranuclear variations. These data provide a detailed neuroanatomic map of cerebral energy metabolism of the septal and anterior hypothalamic regions in animals under standardized conditions.

Abnormalities of cutaneous blood flow regulation in patients with reflex sympathetic dystrophy as measured by laser Doppler fluxmetry.

The response of cutaneous blood flow to autonomic stimuli was evaluated in eight patients with clinically staged reflex sympathetic dystrophy and eight healthy control subjects. Blood flow was measured in the affected and contralateral extremities by laser Doppler fluxmetry. Five autonomic stimuli were applied to the contralateral extremity during blood flow measurement in the ipsilateral affected extremity. Affected limbs of patients with reflex sympathetic dystrophy were found to have statistically significantly increased blood flow during the Valsalva maneuver and cold pressor test, while blood flow decreased in normal controls. No significant differences were found in limb temperature or baseline blood flow between patients and controls. Reflex sympathetic dystrophy stage did not affect response to the procedures. Control subjects demonstrated a rhythmic cycling of cutaneous blood flow that was absent in patients with reflex sympathetic dystrophy. These results support a central abnormality of the sympathetic nervous system in reflex sympathetic dystrophy.

Cerebral air embolism. Report of five cases and review of the literature.

We discuss five patients who had cerebral air embolisms. Clinically, these patients had early seizures, focal neurological findings, or failure to awaken from anesthesia. The patients that survived had minimal neurological deficits. We also discuss the pathophysiology of cerebral air embolism and its differentiation from "the bends." The necessity for recognizing this entity early is important in order to administer appropriate therapy.

Reflex sympathetic dystrophy. A review.

Reflex sympathetic dystrophy is a syndrome of burning pain, hyperesthesia, swelling, hyperhidrosis, and trophic changes in the skin and bone of the affected extremity. It is precipitated by a wide variety of factors in addition to nerve injury. It occurs outside of dermatomal distributions and can spread to involve other extremities without new injury. The diagnosis is primarily clinical, but roentgenography, scintigraphy, and sympathetic blockade can help to confirm the diagnosis. The most successful therapies are directed toward blocking the sympathetic innervation to the affected extremity, in conjunction with physical therapy. The theories proposed to explain the pathophysiology of reflex sympathetic dystrophy include "reverberating circuits" in the spinal cord that are triggered by intense pain, ephaptic transmission between sympathetic efferents and sensory afferents, and the presence of ectopic pacemakers in an injured nerve.

Neuropathic central pain: epidemiology, etiology, and treatment options.

BACKGROUND: Nociceptive pain is a major problem in clinical neurology. Peripheral nerve injury may change the physiology of the dorsal horn so that pain becomes progressively centralized. OBJECTIVE: To review mechanisms underlying the plasticity of dorsal root ganglia and dorsal horn neurons that lead to central pain from a peripheral nerve injury. RESULTS: Evidence is reviewed that points to molecular changes in nociceptive terminals, ectopic firing of afferent pain fibers at the level of the dorsal root ganglia, and physiologic changes of the N-methyl-D-aspartate receptor that cause chronic nociceptive pain. CONCLUSIONS: Central sensitization is the physiologic manifestation of many severe peripherally induced pain states. It is maintained by nociceptive input and a physiologic change in the N-methyl-D-aspartate receptor. It consists of: (1) hypersensitivity at the site of injury; (2) mechanoallodynia; (3) thermal hyperalgesia; (4) hyperpathia; (5) extraterritoriality in the case of complex regional pain syndrome/reflex sympathetic dystrophy; and (6) associated neurogenic inflammation, autonomic dysregulation, and motor phenomena.

Hyperekplexia exacerbated by occlusion of posterior thalamic arteries.

A 65-year-old man with the onset of hyperekplexia at 37 years of age experienced resolution of the illness at the age of 45 years. Twenty years later after a posterior thalamoperforate artery occlusion that produced a "rubral tremor," severe hyperekplexia redeveloped. The patient's symptoms were controlled with clonazepam, except for brief periods. Interruption of the rubrothalamic pathways or neuronal aggregates at the level of the red nucleus seemed to disinhibit the startle reflex.

Progressive multifocal leukoencephalopathy in acquired immune deficiency syndrome.

Progressive multifocal leukoencephalopathy occurred in two homosexual men affected with acquired immune deficiency syndrome (AIDS). Both patients received HLA-matched platelet transfusions in an attempt to increase their immune status, but we were unsuccessful in altering their fatal clinical course.

Neurologic complications of disseminated intravascular coagulation.

Sixty-five patients with a bleeding disorder and coexistent neurologic abnormalities were examined over a 4-year period to determine: (1) the CNS pathology due to disseminated intravascular coagulation (DIC); (2) the clinical setting in which CNS dysfunction due to DIC occurs; and (3) the neurologic complications of DIC as opposed to those patients dying with concurrent DIC. Criteria for inclusion in the study were the combination of: (1) a neurologic disorder in a patient with clinical evidence of a bleeding disorder; and (2) evidence of DIC by laboratory criteria or the detection of fibrin thrombi in multiple organs at postmortem. Twenty-four of 65 patients met these diagnostic criteria, including 14 men and 10 women, aged 24 to 84 years. Autopsies were obtained in 17 patients. These patients were divided into two groups Group I consisted of 10 patients with evidence of cerebral bleeding or infarction at the onset of DIC. Group II consisted of 14 patients who met the diagnostic criteria for DIC but did not demonstrate postmortem evidence of hemorrhage or infarction in the brain. Patients with malignancy who present with findings suggestive of a large-vessel stroke are likely to have DIC and nonbacterial thrombotic endocarditis. The most common neurologic complications of DIC are large vessel occlusion, obtundation and coma, subarachnoid hemorrhage, and multiple cortical and brainstem hemorrhages and infarction.

The movement disorder of reflex sympathetic dystrophy.

We present 43 patients with reflex sympathetic dystrophy (RSD) who manifested abnormalities of movement. The patients have focal dystonia, weakness, spasms, tremor, difficulty initiating movement, and increased tone and reflexes. These motor signs and symptoms may precede other manifestations of the illness by weeks or months. They most frequently, but not invariably, occur concomitantly with sudomotor or vasomotor changes and pain. Lioresal is effective in reducing spasms. Early in the course of RSD, the motor manifestation may be alleviated by intense sympathetic blockade or sympathectomy. In many patients, the movement disorder becomes independent of sympathetic innervation.

The methylphenidate-induced stereotypy in the awake rat: local cerebral metabolism.

The local cerebral metabolic rate for glucose (1=CMRg) was computed in rats with methylphenidate-induced stereotypy using the quantitative 14C-2-deoxyglucose (2-DG) technique. Four rats received methylphenidate 15 mg per kilogram IP. Compared to five control animals, treated rats showed statistically significant (p less than or equal to 0.05) increases in 1-CMRg in globus pallidus, ventral lateral nucleus of the thalamus, subthalamic nucleus, red nucleus, substantia nigra, entopeduncular nucleus, inferior olivary nucleus, and the lateral cerebellar cortex. Significantly, 1-CMRg decreased in area 4 of the motor cortex. The auditory system showed no change in 1-CMRg, demonstrating the specific action of methylphenidate in the rat brain. This technique allows evaluation of the functional anatomy of the entire central nervous system and may be helpful in understanding the mechanisms of methylphenidate-induced stereotypy.

Phenytoin-induced ophthalmoplegia.

Total external ophthalmoplegia was observed in five patients consequent to the oral or intravenous administration of phenytoin. Coincident with the ophthalmoplegia, the state of consciousness varied from drowsiness to coma and the blood levels of phenytoin ranged from 36 to 55 mug per milliliter. Initially, the eyes were fixed in midposition, and oculocephalic and oculovestibular stimulation failed to evoke either horizontal or vertical eye movements. The return of vestibulo-ocular responsiveness lagged behind the return of consciousness and other reflex activity. The mechanism underlying this ophthalmoplegia may be related to the ability of phenytoin to potentiate inhibitory synapses in the vestibulo-oculomotor pathway which utilize gamma aminobutyric acid, and to increase the discharge rate of Purkinge cells which exert an inhibitory influence on the same structures.

Effect of plasma levels of large neutral amino acids and degree of parkinsonism on the blood-to-brain transport of levodopa in naive and MPTP parkinsonian monkeys.

We investigated the transport of levodopa from blood to brain in control and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian monkeys by using intracerebral microdialysis. The degree of parkinsonism was established by the monkey's clinical score and its postmortem striatal dopamine level. We administered levodopa plus carbidopa either orally or by intravenous injection. We estimated the blood-to-brain transport of levodopa as the ratio of its concentration in the brain's extracellular fluid to that in arterial plasma. This ratio was reduced in the MPTP parkinsonian monkeys, and we found an inverse relationship between the monkeys' ability to transport levodopa from blood to brain and their degree of parkinsonism. The oral administration of a high-protein meal or the intravenous infusion of large neutral amino acids before the administration of the levodopa plus carbidopa reduced the transport of levodopa into the brain, as measured by microdialysate collected from the striatum. We found that in two animals an intraperitoneal injection of the beta-adrenergic agonist isoproterenol increased the blood-to-brain transport of levodopa. Pharmacologic manipulation of the transport of levodopa from blood to brain may offer a new strategy for the treatment of Parkinson's disease.

Beta 2-adrenergic agonist as adjunct therapy to levodopa in Parkinson's disease.

We studied the effect of the beta 2-adrenergic agonist albuterol on Parkinson's disease (PD) patients receiving chronic levodopa treatment. The albuterol-treated patients demonstrated reduced parkinsonian symptoms and an increased ability to tap their index finger between two points 20 cm apart, and were able to perform a "walk test" in 70% of their control time. Three patients currently on chronic albuterol therapy still show amelioration of their parkinsonian symptoms, and two have reduced their daily levodopa dose. This study suggests that beta 2-adrenergic agonists as adjunct therapy to levodopa may be beneficial in PD.

Autosomal dominant syndrome of lipid neuromyopathy with normal carnitine: successful treatment with long-chain fatty-acid-free diet.

A family (mother and two sons) have had lifelong muscle weakness and intolerance to fatty food. Histochemistry of muscle biopsies of all three patients demonstrated increased lipids in type I muscle fibers and type II muscle fiber atrophy and paucity. Electronmicroscopy of muscle revealed increased lipids, abnormal mitochondria, and increased lipofuscin granules. Electronmicroscopy of sural nerve showed inclusions in most of the Schwann cell cytoplasm, with lipid droplets, zebra bodies, lipofuscin granules, and abnormal mitochondria. Carnitine and CPT I and II levels were normal in serum and muscle. Treatment with long-chain fatty-acid-free diet resulted in remarkable clinical improvement and in decrease of lipid droplets in the muscle. This dietary program may be useful in other forms of lipid myopathy.

Diagnostic criteria used in studies of reflex sympathetic dystrophy.

OBJECTIVE: Assessment of the diagnostic criteria of reflex sympathetic dystrophy (RSD) and evaluation of the impact of the introduction of the diagnostic criteria of complex regional pain syndrome (CRPS) on the international application of diagnostic criteria of RSD. METHODS: Randomized controlled trials and clinical investigations, published between January 1980 and June 2000, were evaluated with regard to the applied diagnostic criteria of RSD. RESULTS: One hundred seven studies were identified. Thirty-four of these studies were excluded because of inadequate reporting of diagnostic criteria. The 73 included studies were not homogeneous with regard to the diagnostic criteria because they applied many different aspects of sensory and autonomic features. Only 12% of the studies considered the presence of motor features, mostly vaguely described, as mandatory for the diagnosis RSD. Although 10 of the 23 studies published since the introduction of CRPS have applied this term, only 3 used the exact criteria without additions or other modifications. CONCLUSION: Diagnostic criteria sets of RSD focus on many different aspects of sensory and autonomic features that generally are described vaguely. This has not changed since the introduction of the CPRS criteria. These findings question whether the current criteria adequately define RSD.

High-dose cyclophosphamide without stem-cell rescue for refractory CIDP.

Four patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who were refractory to conventional treatment were treated with high-dose cyclophosphamide (200 mg/kg over 4 days). All improved in functional status and muscle strength. Nerve conduction studies improved in three of four. Other immunomodulatory medications have been discontinued. High-dose cyclophosphamide can be given safely to patients with CIDP and patients with disease persistence after standard therapy may have a response that lasts for over 3 years and results in long-term disease remission.

High-dose steroids for perioperative management of patients with myasthenia gravis undergoing thymectomy. A preliminary report.

To eliminate the morbidity associated with thymectomy, we used high-dose corticosteroids perioperatively in 32 patients who had Class II and III myasthenia gravis. All patients were extubated within 2 hours after the operation, and none required respiratory support postoperatively. The average stay in the intensive care unit was 20 hours and the average hospital stay, 6 days. Addition of high-dose corticosteroids to the perioperative managment of patients with myasthenia gravis undergoing thymectomy improved the immediate operative results and eliminated the morbidity associated with this procedure.