Clinical and imaging characterization of progressive spastic dysarthria.

BACKGROUND AND PURPOSE: To describe speech, neurological and imaging characteristics of a series of patients presenting with progressive spastic dysarthria as the first and predominant sign of a presumed neurodegenerative disease. METHODS: Participants were 25 patients with spastic dysarthria as the only or predominant speech disorder. Clinical features, pattern of MRI volume loss on voxel-based morphometry and pattern of hypometabolism on F18-fluorodeoxyglucose positron emission tomography (FDG-PET) scan are described. RESULTS: All patients demonstrated speech characteristics consistent with spastic dysarthria, including strained voice quality, slow speaking rate, monopitch and monoloudness, and slow and regular speech alternating motion rates. Eight patients did not have additional neurological findings on examination. Pseudobulbar affect, upper motor neuron pattern limb weakness, spasticity, Hoffman sign and positive Babinski reflexes were noted in some of the remaining patients. Twenty-three patients had electromyographic assessment and none had diffuse motor neuron disease or met El Escorial criteria for amyotrophic lateral sclerosis. Voxel-based morphometry revealed striking bilateral white matter volume loss affecting the motor cortex (BA 4), including the frontoparietal operculum (BA 43) with extension into the middle cerebral peduncle. FDG-PET showed subtle hypometabolism affecting the premotor and motor cortices in some patients, particularly in those who had a disease duration longer than 2 years. CONCLUSIONS: A neurodegenerative disorder that begins focally with spastic dysarthria due to involvement of the motor and premotor cortex and descending corticospinal and corticobulbar pathways is characterized. The descriptive label 'progressive spastic dysarthria' to best capture the dominant presenting feature of the syndrome is proposed.

Proboscis lateralis.

INTRODUCTION: Proboscis lateralis is a rare congenitally acquired facial abnormality characterized by a soft-tissue tube- or trunk-like appendage projecting from the surface of the face, most frequently rooted in the medial canthal region. Proboscis lateralis is generally associated with a wide range of concomitant craniofacial anomalies, giving rise to multiple theories describing the embryological pathogenesis and various classification systems to account for the pathological associations. RESULTS/CONCLUSION: This paper provides a literature review of the rare manifestations of proboscis lateralis and represents a summary of current literature related to embryological pathogenesis, definitive diagnosis, and surgical management approaches.

Cervical spine MR imaging findings of patients with Hirayama disease in North America: a multisite study.

BACKGROUND AND PURPOSE: Most studies of HD have been conducted in Asia, particularly Japan. To characterize the MR imaging findings of North American patients with HD, we reviewed neutral and flexion cervical MR imaging examinations performed for possible HD at 3 academic medical centers located in the Southeastern, Southwestern, and Midwestern regions of the United States. MATERIALS AND METHODS: Three neuroradiologists assessed the MR imaging examinations in a blinded fashion and reached a consensus rating for LOA of the posterior dura to the spine, lower spinal cord atrophy, spinal cord T2 hyperintensity, loss of cervical lordosis, anterior dural shift with flexion, and confidence of imaging diagnosis. Final reference diagnosis was established separately with a retrospective chart review by a neurologist. RESULTS: Twenty-one patients met the criteria for HD, all were North American males and all who reported their race were white. Seventeen patients did not meet the criteria and served as controls. Four imaging attributes, LOA, dural shift with flexion, consensus diagnosis of neutral images, and consensus diagnosis of combined neutral and flexion images were all able to discriminate the group with HD from the group without HD (P < .05 for each). Findings of HD were often present on neutral images, but the addition of flexion images increased diagnostic confidence. CONCLUSIONS: MR imaging findings in white North American patients with HD include LOA on neutral images and forward displacement of the dura with flexion. Findings are often present on neutral MR images and, in the appropriate clinical scenario, should prompt flexion MR imaging to evaluate anterior dural shift.

Predicting survival in frontotemporal dementia with motor neuron disease.

OBJECTIVE: To determine whether clinical and demographic features are associated with prognosis in patients with frontotemporal dementia and motor neuron disease (FTD-MND). METHODS: This was a case series of FTD-MND categorized according to behavioral- or language-dominant symptoms at presentation and throughout the disease course. Demographic, clinical, imaging, and survival data were analyzed with respect to dominant FTD-MND type. Voxel-based morphometry was used to assess and compare regional patterns of atrophy in behavioral- and language-dominant FTD-MND types. RESULTS: Of the 56 patients with FTD-MND who were identified, 31 had dominant behavioral symptoms and 25 had dominant language symptoms; 53 patients had died. A survival difference was present between types, with patients with behavioral-dominant symptoms surviving 506 days longer than patients with language-dominant symptoms (mean 1,397 vs 891 days; p = 0.002). There was also a difference in time from diagnosis to death (p = 0.02) between groups. Patients with language-dominant disease were more likely to have bulbar-onset than limb-onset motor neuron disease (MND) (p = 0.01). There was a similar pattern of frontal and temporal lobe atrophy in both types, although there was some evidence for the behavioral type to have more frontal atrophy and the language type to have more left temporal atrophy. CONCLUSIONS: In our series of patients with FTD-MND, language-dominant FTD-MND was associated with bulbar-onset MND and a shorter survival. There was also evidence that the dominant FTD-MND type is related to differences in brain atrophy patterns.

Clinically suspected fibrocartilaginous embolism: clinical characteristics, treatments, and outcomes.

OBJECTIVE: To study the frequency, demographics, clinical characteristics, and outcomes of patients with an antemortem diagnosis of fibrocartilaginous embolism (FCE), a rare cause of spinal cord and cerebral infarction because of the presumed embolization of nucleus pulposus material into the vascular circulation. METHODS: We retrospectively reviewed the institutional experience of patients who received an antemortem diagnosis of FCE by their treating physician at the Mayo Clinic (Rochester, MN, USA) from 1997 to 2009. All patients underwent laboratory, radiological, and clinical exclusion of other possible and related diagnoses. RESULTS: Of 164 patients with acute spinal cord infarction seen during the study timeframe, 9 (5.5%; 95% CI 2.5, 10.2%) met inclusion criteria for high likelihood of FCE (6 men, 3 women; median age 46 years old, range 21-64). All patients were severely affected (median modified Rankin Scale 4, median Barthel index 45; mean time to evaluation 57 days). One patient (1/9) experienced concomitant cerebral infarction. No patients had noticeable improvement from steroid treatment. CONCLUSION: The diagnosis of FCE in life is common at this referral center, accounting for 5.5% of all cases of acute spinal cord infarction seen. Although FCE is a postmortem diagnosis, we propose clinical criteria for FCE in life to better characterize the relatively high number of patients with unexplained ischaemic myelopathy.

Cholinergic modulation of non-N-methyl-D-aspartic acid glutamatergic transmission in the chick ventral lateral geniculate nucleus.

Neurotransmission between glutamatergic terminals of retinal ganglion cells and principal neurons of the ventral lateral geniculate nucleus (LGNv) was examined with patch clamp recordings in chick brain slices during electrical stimulation of the optic tract. Since muscarinic and nicotinic receptors are present in high densities in LGNv, the present study examined possible roles of both receptors in modulating retinogeniculate transmission. During whole-cell recordings from LGNv neurons, acetylcholine (ACh, 100 microM) caused an initial increase in amplitudes of optic tract-evoked non-N-methyl-D-aspartic acid (NMDA) glutamatergic postsynaptic currents (PSCs). This increase was unchanged when 1 microM atropine was present, indicating that this initial enhancement of PSCs was due entirely to activation of nicotinic receptors. However, during washout of ACh the amplitudes of evoked PSCs became significantly decreased by 40.4+/-5.0% for several minutes before recovering to their original amplitudes, an effect blocked by 1 microM atropine. Exogenously applied muscarine (10 microM) markedly depressed optic tract-evoked PSCs, and this decrease in amplitude was blocked by atropine. In a second set of experiments, we examined effects of releasing endogenous ACh prior to optic tract stimulation. This was accomplished by stimulation of the lateral portion of LGNv via a separate conditioning electrode. Following a brief train of low intensity conditioning stimuli, non-NMDA glutamatergic PSCs evoked by optic tract stimulation were potentiated. However, at higher conditioning stimulus intensities the PSCs were markedly decreased compared with control, and this decrease was partially blocked by atropine (1 microM). Neither ACh nor muscarine altered amplitudes of PSCs elicited by exogenously applied glutamate. Muscarine significantly reduced the frequency but not the amplitudes of miniature PSCs, consistent with a presynaptic location for muscarinic receptors mediating these effects. Thus while activation of nicotinic receptors potentiates retinogeniculate transmission, activation of muscarinic receptors mediates depression of transmission, demonstrating a complex cholinergic modulation of sensory information in LGNv.

Subcutaneous IGF-1 is not beneficial in 2-year ALS trial.

BACKGROUND: Previous human clinical trials of insulin-like growth factor type I (IGF-1) in amyotrophic lateral sclerosis (ALS) have been inconsistent. This phase III, randomized, double-blind, placebo-controlled study was undertaken to address whether IGF-1 benefited patients with ALS. METHODS: A total of 330 patients from 20 medical centers were randomized to receive 0.05 mg/kg body weight of human recombinant IGF-1 given subcutaneously twice daily or placebo for 2 years. The primary outcome measure was change in their manual muscle testing score. Secondary outcome measures included tracheostomy-free survival and rate of change in the revised ALS functional rating scale. Intention to treat analysis was used. RESULTS: There was no difference between treatment groups in the primary or secondary outcome measures after the 2-year treatment period. CONCLUSIONS: Insulin-like growth factor type I does not provide benefit for patients with amyotrophic lateral sclerosis.

Misdirection of regenerating motor axons after nerve injury and repair in the rat sciatic nerve model.

Misdirection of regenerating axons is one of the factors that can explain the poor results often found after nerve injury and repair. In this study, we quantified the degree of misdirection and the effect on recovery of function after different types of nerve injury and repair in the rat sciatic nerve model; crush injury, direct coaptation, and autograft repair. Sequential tracing with retrograde labeling of the peroneal nerve before and 8 weeks after nerve injury and repair was performed to quantify the accuracy of motor axon regeneration. Digital video analysis of ankle motion was used to investigate the recovery of function. In addition, serial compound action potential recordings and nerve and muscle morphometry were performed. In our study, accuracy of motor axon regeneration was found to be limited; only 71% (+/-4.9%) of the peroneal motoneurons were correctly directed 2 months after sciatic crush injury, 42% (+/-4.2%) after direct coaptation, and 25% (+/-6.6%) after autograft repair. Recovery of ankle motion was incomplete after all types of nerve injury and repair and demonstrated a disturbed balance of ankle plantar and dorsiflexion. The number of motoneurons from which axons had regenerated was not significantly different from normal. The number of myelinated axons was significantly increased distal to the site of injury. Misdirection of regenerating motor axons is a major factor in the poor recovery of nerves that innervate different muscles. The results of this study can be used as basis for developing new nerve repair techniques that may improve the accuracy of regeneration.

A clinical trial of creatine in ALS.

BACKGROUND: Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons. METHODS: The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale-Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly. RESULTS: Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials. CONCLUSION: Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS.

Regional anesthesia does not increase the risk of postoperative neuropathy in patients undergoing ulnar nerve transposition.

UNLABELLED: The use of regional anesthetic techniques in patients with preexisting neuropathies has been widely debated. The possibility of needle- or catheter-induced trauma, local anesthetic toxicity, or neural ischemia during regional blockade may place patients with underlying mechanical, ischemic, or metabolic neurologic derangements at increased risk of progressive neural injury. We evaluated the safety of regional versus general anesthesia in patients with a preexisting ulnar neuropathy undergoing ulnar nerve transposition. All patients (n = 360) who underwent ulnar nerve transposition at the Mayo Clinic from 1985 to 1999 were retrospectively studied. A general anesthetic was performed in 260 (72%) patients. The remaining 100 (28%) patients received an axillary block, including 64 patients in whom an ulnar paresthesia or nerve stimulator motor response was elicited at the time of block placement. Patient characteristics, the severity of preoperative ulnar nerve dysfunction, and surgical variables were similar between groups. Anesthetic technique did not affect neurologic outcome (new or worsening pain, paresthesias, numbness, or motor weakness) immediately after surgery or at 2 or 6 wk after surgery. All six patients in the Axillary Block group who reported new or worsening neurologic symptoms after surgery had received bupivacaine in combination with either an ulnar paresthesia or motor response. By using logistic regression, bupivacaine was identified as an independent risk factor for worsening of ulnar nerve function compared with other local anesthetics. We conclude that axillary blockade is a suitable anesthetic technique for this procedure. IMPLICATIONS: The use of regional anesthetic techniques in patients with preexisting neuropathies has been widely debated. Theoretical concerns include the risk of progressive nerve damage from direct needle trauma or local anesthetic toxicity. This investigation, however, supports the safety of axillary blockade in patients with preexisting ulnar neuropathy undergoing ulnar nerve transposition.

Suramin-induced neuropathy in an animal model.

Suramin is being used either alone, or in combination with other chemotherapeutic agents, in the treatment of hormone-refractory or metastatic prostate cancer. Use of this potentially valuable chemotherapy is limited by a dose-dependent polyneuropathy. It has been difficult in human studies to characterize peripheral suramin toxicity separately from cancer-related neuropathy. To characterize suramin-induced neuropathy in a rat model, adult rats were given either a single dose of 500 mg/kg (high dose) or 50 mg/kg (low dose) weekly suramin for 2 months. Electrophysiology and peroneal/sural nerve morphometry were performed. In high dose animals, neuropathy developed within 2 weeks, most severe in the digital sensory responses (DSR) (p<0.05) and tail and hind limb compound muscle action potential (p<0.001). Histologically, there was evidence of axonal degeneration and axon atrophy. With low dose suramin, the DSR (p<0.05) and tail distal sensory and motor responses (p<0.01) were most severely affected at 2 months. Axonal degeneration was seen in teased fibers from most animals. With TEM, there were abundant characteristic lysosomal inclusion bodies in DRG and Schwann cells. Electrophysiological and histological evidence of peripheral demyelination was rare, being observed in only one animal. Suramin induced a length, dose and time-dependent axonal sensorimotor polyneuropathy associated with axonal degeneration, atrophy, and accumulation of glycolipid lysosomal inclusions.

Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis.

BACKGROUND: Preclinical and clinical studies of gabapentin in patients with ALS led the authors to undertake a phase III randomized clinical trial. METHODS: Patients were randomly assigned, in a double-blinded fashion, to receive oral gabapentin 3,600 mg or placebo daily for 9 months. The primary outcome measure was the average rate of decline in isometric arm muscle strength for those with two or more evaluations. RESULTS: Two hundred four patients enrolled, 196 had two or more evaluations, and 128 patients completed the study. The mean rate of decline of the arm muscle strength was not significantly different between the groups. Moreover, there was no beneficial effect upon the rate of decline of other secondary measures (vital capacity, survival, ALS functional rating scale, timed walking) nor was there any symptomatic benefit. In fact, analysis of the combined data from the phase II and III trials revealed a significantly more rapid decline of forced vital capacity in patients treated with gabapentin. CONCLUSION: These data provide no evidence of a beneficial effect of gabapentin on disease progression or symptoms in patients with ALS.

alpha7-Containing nicotinic receptors are segregated to the somatodendritic membrane of the cholinergic neurons in the avian nucleus semilunaris.

Segregation of ion channels and neurotransmitter receptors is an important mechanism for determining the functionality of the nervous system. In the case of nicotinic acetylcholine receptors, electrophysiological and anatomical studies have demonstrated that these receptors can be located at the somatodendritic and the axon terminal portions of neurons. Functionally, somatodendritic nicotinic receptors mediate fast excitatory transmission and possibly regulate other cell functions, while presynaptic nicotinic receptors enhance the release of neurotransmitters from axon terminals. Neurons in the mesencephalic lateral spiriform nucleus of the chick do not appear to restrict the localization of nicotinic receptors to specific membrane compartments, since receptors containing alpha5 and/or beta2 subunits are found both on the cell bodies and on the axonal projections of these neurons [Torrao A. S. et al. (1996) Brain Res. 743, 154-161]. We report here that, in contrast to lateral spiriform neurons, neurons in the nucleus semilunaris do appear to compartmentalize nicotinic receptors. The cholinergic nucleus semilunaris neurons express a high density of alpha7-containing nicotinic receptors on their somas [Britto L. R. G. et al. (1992) J. comp. Neurol. 317, 325-340]. However, when we examined the projections of these neurons in the lateral spiriform nucleus, we found no evidence for expression of alpha7-containing receptors on the cholinergic fibers from nucleus semilunaris neurons. Furthermore, patch-clamp electrophysiological recording from lateral spiriform neurons indicated an absence of presynaptic alpha7-containing nicotinic receptors capable of modulating the release of acetylcholine. We conclude that neurons are capable of segregating alpha7-containing nicotinic receptors to specific areas of their plasma membrane. Such targeting of nicotinic receptors would play an important role in determining their functional role in neurons.

Role of redox-active iron ions in the decomposition of S-nitrosocysteine in subcellular fractions of porcine aorta.

We recently reported that degradation of S-nitrosocysteine in homogenates of porcine aorta increased severalfold in the presence of Mg2+ ions [Kostka, P., Xu, B. & Skiles, E.H. (1999) J. Cardiovasc. Pharmacol. 33, 665-670]. The objective of the present study was to examine this in greater detail. The rate of S-nitrosocysteine degradation by aortic homogenates in the presence of Mg2+ ions exhibited differential sensitivity to chelators of iron ions. Terpyridine and diethylenetriamine penta-acetic acid (5-500 microM) caused a concentration-dependent inhibition of S-nitrosocysteine decay, whereas deferoxamine (100 microM) was ineffective. o-Phenanthroline (250 microM), a selective chelator of Fe2+ ions, potentiated the reaction at low initial concentrations of S-nitrosocysteine (< or = 15 microM) and inhibited the reaction at higher concentrations. The inhibitory effects of o-phenanthroline were related to suppression of S-nitrosocysteine decay by cysteine-mediated reduction of Fe3+. In the presence of o-phenanthroline, S-nitrosocysteine decomposition followed saturable kinetics with K0.5 = 3.8 +/- 0.3 microM and h = 1.8 +/- 0.1 (mean +/- SE, n = 4). Comparison of the rates of S-nitrosocysteine decay in different subcellular fractions showed selective association with the cytosolic fraction, as documented by copurification with lactate dehydrogenase activity. At non-limiting concentrations of S-nitrosocysteine, the rate of degradation in the cytosolic fraction was 4.1 +/- 0.3 nmol.min-1.(mg protein)-1 (n = 4). It is concluded that the cytosolic fraction of porcine aorta contains a protein factor, presumably an enzyme, capable of catalyzing heterolytic decomposition of the S-NO bond of S-nitrosocysteine in a process involving redox cycling of iron ions.

Fulminant case of hereditary neuropathy with liability to pressure palsy.

Hereditary neuropathy with liability to pressure palsy (HNPP) is typified as isolated nerve palsies caused by trivial compression or trauma. It rarely presents in two extremities and even more infrequently affects all four limbs simultaneously. We present a patient who concurrently experienced right shoulder, left hand, and bilateral foot weakness mimicking several multifocal conditions. Electromyography suggested HNPP and subsequent nerve biopsy and genetic testing were confirmatory. The case demonstrates that HNPP can present in a fulminant manner and should be included in the differential diagnosis of acute multiple mononeuropathies. The possible causes for such a rapid clinical course in our patient are discussed.

Fast excitatory nicotinic transmission in the chick lateral spiriform nucleus.

The lateral spiriform nucleus (SpL) in the chick mesencephalon contains functional nicotinic receptors and receives a cholinergic fiber projection. We now use double-label immunohistochemistry to demonstrate that choline acetyltransferase-immunopositive fibers in the SpL and in the cholinergic fiber tract lateral to the nucleus are associated with fibers expressing the alpha5 and/or alpha3 nicotinic receptor subunits as determined by mAb35 immunoreactivity. This morphological evidence suggests that there might be synapses between the cholinergic fibers and the dendrites of SpL neurons. Whole-cell recordings from SpL neurons in current-clamp mode revealed EPSPs evoked by stimulation of the cholinergic fiber tract lateral to the SpL. These EPSPs increased in amplitude in the presence of bicuculline. Further addition of the nicotinic antagonist dihydro-beta-erythroidine (DHbetaE) to the buffer significantly attenuated them. Almost all of the remaining EPSP was blocked by 6,7-dinitroquinoxaline-2,3-dione. In the presence of an antagonist cocktail that isolated the nicotinic responses, a fast, monosynaptic nicotinic EPSP or EPSC was evoked. In some neurons, the nicotinic EPSP resulted in the generation of an action potential. The nicotinic nature of the evoked response was confirmed by blockade of the EPSPs or EPSCs with nicotinic antagonists, including DHbetaE, D-tubocurare, and mecamylamine. The nicotinic response was insensitive to low concentrations (10-100 nM) of methyllycaconitine, indicating that typical alpha7-containing receptors were not involved. The results demonstrate that endogenously released acetylcholine generates EPSPs that can elicit action potentials by acting at postsynaptic nicotinic receptors on SpL neurons.

Postsynaptic nicotinic receptors on dopaminergic neurons in the substantia nigra pars compacta of the rat.

Previous studies have shown that application of nicotinic agonists in the substantia nigra pars compacta increases the firing rate of dopaminergic neurons. We have used intracellular recordings to show that the response of these neurons to nicotine is postsynaptic, since it persists in the presence of low-calcium buffer containing tetrodotoxin. Burst firing in the presence of nicotine was not observed. The presence of postsynaptic nicotinic receptors was confirmed by immunohistochemical localization of the alpha4 nicotinic receptor subunit on dendrites in the substantia nigra pars compacta. The majority of tyrosine hydroxylase-immunopositive neurons in the substantia nigra pars compacta were also immunopositive for the alpha4 subunit. Immunohistochemical localization of the alpha4 and beta2 subunits in adjacent brain sections produced similar patterns of staining. Electron micrographs clearly indicated the presence of alpha4 subunit at postsynaptic densities. The predominant role of nicotinic receptors in the central nervous system has been suggested to be the presynaptic modulation of neurotransmitter release [McGehee D. S. and Role L. W. (1995) A. Rev. Physiol. 57, 521-546]. Although several postsynaptic nicotinic responses have also been reported in the literature, it is unclear as to whether the postsynaptic nicotinic receptors mediating responses to exogenously applied agonists are involved in synaptic transmission. From our electrophysiological and immunohistochemical results, we conclude that alpha4-containing nicotinic receptors are found at synapses on dopaminergic neurons. These synapses are similar to the cholinergic synapses described at these neurons, suggesting that nicotinic receptors are important in modulating the excitability of dopaminergic neurons by direct synaptic transmission.

Acute bilateral infarcts of the posterior inferior cerebellar artery.

Acute bilateral infarcts in the territory of the posterior inferior cerebellum artery are rare and poorly documented in the literature. Thus, this report describes the clinical course and outcome in 3 patients. Although one was associated with coronary artery bypass surgery, the etiology was not known. Despite large territorial infarcts, the patients recovered to ambulation with minimal assistance.

Clinical features of perineuritis.

We report 13 patients with pathologically confirmed perineuritis. Seven patients had diabetes mellitus, 5 had nutritional abnormalities, 2 had associated rheumatological illnesses, 2 had sepsis with multiorgan failure, and 1 had a history of malignancy. Electrophysiologic testing demonstrated mononeuritis multiplex in 7, demyelinating neuropathy in 4, distal sensory and motor neuropathy in 1, and polyradiculoneuropathy in 1. Twelve patients received immunomodulating therapy with variable responses. We conclude that perineuritis is associated with a number of different systemic conditions and several clinical patterns of peripheral neuropathy. Response to immunomodulation is variable. The most frequent association is with diabetes mellitus, a previously unrecognized association.