Search

Objective: To define the clinicopathologic features of amphiphysin-immunoglobulin G (IgG)-mediated neuropathy., Methods: Patients examined at our institution from January 1, 1995, to September 30, 2018, with amphiphysin-IgG by indirect immunofluorescence and Western blot, were reviewed. Their phenotypes were compared to cases of coexisting collapsin response-mediator protein-5 (CRMP5)-IgG or anti-neuronal nuclear antibody type 1 (ANNA1-IgG) and CRMP5-IgG autoimmunity. Improvement in modified Rankin Scale (mRS) (≥1) on follow-up was considered a favorable outcome. Amphiphysin RNA expression was assessed in healthy nerves., Results: Fifty-three amphiphysin-IgG-positive cases were identified. Of 33 (60%) patients with neuropathy, 21 had amphiphysin-IgG alone, and 12 had coexisting autoantibodies (ANNA1-IgG, n = 8; CRMP5-IgG, n = 2; ANNA1-IgG and CRMP5-IgG, n = 2). The neuropathies in isolated amphiphysin-IgG autoimmunity included polyradiculoneuropathy (62%), diffuse sensory neuronopathy (35%), and facial neuropathy with gastroparesis (3%). Among these, pain (80%), breast cancer (63%), and CNS (57%) involvements commonly coexisted, and neuropathy frequently prompted breast cancer diagnosis (76%). Stiff-person spectrum disorder was the most common CNS accompaniment (45%). Nerve biopsies showed axonal loss (n = 6/6), subperineurial edema (n = 4/6), and CD4 predominant inflammation (n = 2/6). Median mRS score at last follow-up was 3.5; 58% of patients were immunotherapy-responsive. Patients with amphiphysin-IgG alone had more favorable immunotherapy response than patients with CRMP5-IgG polyneuropathy (n = 45) (44% vs 16%, p = 0.028, odds ratio 4.2, 95% confidence interval 1.1 to 15.5). Only 1/9 (11%) patients with amphiphysin-IgG with coexisting CRMP5-IgG or ANNA1-IgG had immunotherapy response. RNA amphiphysin expression occurred at low levels in nerve., Conclusion: Amphiphysin-IgG autoimmune neuropathy has a recognizable phenotype, is frequently immune responsive, and can prompt early diagnosis of breast cancer., (© 2019 American Academy of Neurology.)

Objective: To assess feasibility of noninvasive in vivo reflectance confocal microscopy (RCM) of Meissner corpuscles (MCs) as a measure of sensory neuropathy (SN)., Background: MCs are touch-pressure sensation receptors in glabrous skin. Skin biopsy studies suggest that fingertip MC density (MCs/mm(2)) is a sensitive measure of diabetic and idiopathic SN. In vivo RCM of skin is an emerging field, with applications including evaluation of cancer. It is painless and noninvasive. Feasibility of in vivo RCM of MCs has not been explored., Methods: Fifteen adults (10 controls, 5 SN subjects) underwent in vivo RCM at the fingertip (Digit V) and thenar eminence. In vivo RCM was conducted to determine whether MCs were visible within dermal papillae and, if visible, to characterize their imaging appearance and assess MCs/mm(2) at each site., Results: MCs were identified in dermal papillae at all sites in controls. MCs appeared as heterogeneous bright structures within dermal papillae, which appeared as dark "pits." Mean MC density in controls was 12 +/- 5.3/mm(2) (Digit V) and 5.1 +/- 2.2/mm(2) at the thenar eminence. MC density in SN was lower than controls at Digit V (2.8 +/- 5.7/mm(2), p = 0.01) and the thenar eminence (1.4 +/- 1.1/mm(2), p = 0.004). MCs were absent in a sensory neuronopathy; milder reductions in MC density were seen among diabetic and HIV-positive subjects., Conclusions: Meissner corpuscles (MCs) can be visualized and quantitated in controls and sensory neuropathy (SN) using in vivo reflectance confocal microscopy (RCM). In vivo RCM of MCs has potential for noninvasive detection and monitoring of SN, if subsequent studies show that with denervation or reinnervation, reliable and recognizable changes or loss can be detected using our described approaches.

Background: Activation of effector T lymphocytes, mediated in part by costimulatory molecules, is an important mechanism in the pathogenesis of immune-mediated diseases of the peripheral nervous system (PNS)., Objective: To analyze the expression and distribution pattern of the inducible costimulator (ICOS), a recently identified costimulatory molecule implicated in T-cell activation, and its unique ligand (ICOS-L), in inflammatory disorders of the PNS., Methods: We studied RNA and protein expression in sural nerve biopsy specimens from patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and vasculitic neuropathy (VN) vs patients with hereditary neuropathies (HNs) serving as a noninflammatory control using reverse-transcriptase PCR and immunohistochemistry. In addition, in vitro analysis was performed by flow cytometry., Results: ICOS and ICOS-L mRNA was found to be significantly upregulated in samples from patients with GBS, CIDP, and VN compared to HNs. Immunohistochemistry identified T lymphocytes as the cellular source of ICOS, whereas macrophages expressed the corresponding ligand ICOS-L. Further analysis revealed that the distribution of ICOS-expressing T cells did not differ between acute and chronic inflamed PNS diseases. Correspondingly, the expression pattern of ICOS-L was similar in the inflamed tissues but differed significantly when compared to HNs., Conclusions: Inducible costimulator, expressed by T lymphocytes, and inducible costimulator ligand, expressed by macrophages within the peripheral nerve, might not only be relevant in inducing an acute immune response but might also be critically involved in perpetuating inflammation in chronically immune-mediated disorders of the peripheral nervous system.

Objective: To report the clinical, electrophysiologic, and histologic characteristics of subacute inflammatory demyelinating polyneuropathy (SIDP) and to present the diagnostic criteria of this disease., Methods: For a diagnosis of "definite SIDP," there were four mandatory criteria: 1) progressive motor and/or sensory dysfunction consistent with neuropathy in more than one limb with time to nadir between 4 and 8 weeks, 2) electrophysiologic evidence of demyelination in at least two nerves, 3) no other etiology of neuropathy, and 4) no relapse on adequate follow-up. Supportive criteria included high spinal fluid protein level (>55 mg/dL) and inflammatory cells in the nerve biopsy. A diagnosis of "probable SIDP" required progression of demyelinating neuropathy over a 4- to 8-week period., Results: Sixteen definite SIDP patients were identified among 29 probable SIDP patients. An antecedent infection was found in 38% of cases. The two most common neuropathy types were a symmetric motor-sensory neuropathy and a pure motor neuropathy. Cranial nerve deficits and respiratory failure were rare. Spinal fluid protein was high in 93% of cases. Demyelination was documented by the motor nerve conduction in 88% of cases and by the near-nerve needle sensory nerve conduction in two cases. Almost all patients were treated with prednisone and some with additional immunotherapies. Complete recovery was achieved in 69% of cases and partial recovery in others. Definite SIDP had all the characteristics of CIDP with three exceptions: a higher rate of antecedent infection, no relapse rate, and a high rate of recovery to normal., Conclusion: Subacute inflammatory demyelinating polyneuropathy is a definite entity bridging the gap between Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.

The authors describe the clinical course, postmortem findings, and characterization of a novel autoantibody (anti-M-phase phosphoprotein-1 [anti-MPP-1]) in a patient with a longstanding acquired demyelinating polyneuropathy and neuronopathy. Postmortem examination identified active sensory neuron degeneration, sensory axon loss, and widespread peripheral nerve demyelination. A possible pathophysiologic role of anti-MPP-1 is not yet identified.

Objective: To evaluate morphologic changes in small endoneurial vessels in patients with autoimmune demyelinative neuropathy and antiglycosphyngolipid antibodies., Background: Although a humoral immune cause has been postulated for various demyelinating neuropathies, the mechanism by which large molecules like immunoglobulins can traverse the blood-nerve barrier (BNB) to enter the endoneurium is not understood., Methods: We examined histologic and ultrastructural changes in small endoneurial vessels in sural nerve biopsy specimens from autoimmune demyelinative neuropathy patients, with or without anti-glycosphingolipid (GSL) antibodies. Density of small endoneurial vessels, mean endothelial area, mean luminal area, and the percentage of endothelial cell junctions (that make up the BNB) that showed evidence of disruption were evaluated., Results: Only junctional disruption showed a significant difference: autoimmune demyelinative neuropathy patients with anti-GSL antibodies showed more BNB disruption than autoimmune demyelinative neuropathy patients without antibodies or control patients with nonautoimmune neuropathies. The most commonly observed endoneurial change in antibody-positive autoimmune demyelinative neuropathy patients was the finding of continuous, patent spaces lacking tight junctions between endothelial cells., Conclusions: Brain endothelial cells and endoneurial endothelial cells share various GSL antigens, including GM1 and GD1b gangliosides, with peripheral nerve tissues. Circulating anti-GSL antibodies could damage cell-to-cell attachments in endoneurial endothelium. This barrier disruption may permit the large molecules like immunoglobulins to enter the endoneurial space, contributing to development of autoimmune demyelinative neuropathy.

Objective: To determine the expression pattern and cellular source of matrix metalloproteinases (MMPs) in chronic inflammatory demyelinating polyneuropathy (CIDP) and nonsystemic vasculitic neuropathy (NSVN)., Background: MMPs are endopeptidases involved in tissue destruction and infiltration by immune cells in multiple sclerosis and Guillain-Barré syndrome. Enzyme inhibitors of MMPs attenuate clinical symptoms in corresponding animal models of these diseases. MMP inhibition may therefore be a novel approach for the treatment of CIDP and NSVN. However, the spectrum of MMPs expressed in chronic inflammatory neuropathies has not been established., Methods: The expression of MMP-2, MMP-3, MMP-7, and MMP-9 in T cells, macrophages, and stromal cells in CIDP, NSVN, and noninflammatory neuropathies (NIN) was quantitated by immunohistochemistry. Results were correlated with clinical and electrophysiologic findings., Results: The production of MMP-2 and MMP-9 is increased in nerve tissue in CIDP and NSVN compared with NIN. T cells are the predominant source of MMP-2 and MMP-9 in CIDP and NSVN, whereas macrophages contribute only to a minor extent. Stromal cells of the perineurium/epineurium are an additional source of MMP-2 in NSVN, but not in CIDP. Expression of MMP-3 and MMP-7 was not detectable in CIDP or NSVN. Expression of MMP-2 and MMP-9 did not correlate with clinical disease activity and electrophysiologic measurements., Conclusions: The upregulation of MMP-2 and MMP-9 is a specific feature of CIDP and NSVN, and selective inhibitors of these enzymes could be used to prevent inflammatory tissue damage. The similar increase of MMP-2 and MMP-9 in both demyelinating (CIDP) and nondemyelinating (NSVN) neuropathies raises doubts about whether MMPs play a primary role in demyelination.

An unusual clinical manifestation of nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is described. A patient with a 13-year history of CIDP developed diplopia and proptosis. Imaging of the neuraxis showed marked bilateral trigeminal nerve hypertrophy and lumbosacral nerve root hypertrophy. Biopsy of the right infraorbital nerve revealed inflammatory infiltrates and extensive onion bulb formation, consistent with CIDP.

The presence of inexcitable motor nerves early in the course of Guillain-Barré syndrome (GBS) identifies a subgroup of patients with more severe disease and delayed recovery. How frequently these electrodiagnostic findings reflect a primary axonal attack ("axonal" GBS) is controversial. We present two children with severe acute GBS, delayed recovery, and residual disability despite early treatment with human immunoglobulin. They had inexcitable motor nerves at days 6 and 7, and profuse fibrillations and positive waves on subsequent studies. Clinically and electrodiagnostically, both children's disease resembled the acute motor-sensory axonal variant of GBS (AMSAN). Sensory and motor nerve biopsies revealed severe macrophage-associated demyelination with axonal degeneration of variable severity. We conclude that clinical and electrodiagnostic features cannot discriminate between the "axonal" and demyelinating GBS. Early and severe demyelination with secondary axonal damage may mimic clinically and electrophysiologically the AMSAN variant of GBS.

We assessed the frequency and extent of axonal involvement in the ventral spinal roots in 15 Japanese autopsied patients with Guillain-Barré syndrome (GBS). Teased-fiber preparation revealed that five had predominantly axonal pathology with minimal segmental demyelination, seven had predominantly segmental demyelination with minimal axonal changes, two patients showed a mixture of both conditions, and one patient did not show any particular pathologic changes. We confirmed axon loss by immunohistochemical analysis of high-molecular-weight neurofilament protein. Macrophage invasion was a prominent feature in nerves with predominantly axonal changes. Two patients with severe axonal involvement and prolonged clinical courses exhibited motor neuron loss with astrogliosis in the ventral horns. These results suggest that autopsy-verified axonal involvement is more frequent among Japanese GBS patients than in Caucasian populations but less frequent than that reported from northern China.

During 1 year, we used immunocytochemical staining of human cerebellum to screen 1,488 serums for IgG autoantibodies to Hu and Yo antigens. Three serums had none of the classically described patterns of IgG binding but instead, selectively stained the cerebellar molecular layer. Evaluation of clinical data showed that the patients had either typical Miller Fisher syndrome (MFS) or Guillain-Barré syndrome with ophthalmoplegia. Further analysis by ELISA, assay showed that all three serums had high titers of IgG anti-GQ1b autoantibodies. IgG autoantibody staining of human cerebellum, which is used for the diagnosis of paraneoplastic disorders, may have additional specificity for other, presumably autoimmune, syndromes such as MFS. The specificity of the serum IgG autoantibody binding to the cerebella molecular layer may be related to the ataxia that often occurs in these patients.

Nerve root enhancement of the cauda equina occurs in Guillain-Barré syndrome (GBS), but the frequency, diagnostic value, and meaning of this finding is unknown. We prospectively obtained gadolinium-enhanced lumbosacral spine MRIs in 24 consecutive patients with acute GBS and blindly rated nerve root enhancement as absent, mild, or prominent. The MRIs were obtained 13 days, mean, after onset of symptoms (range 2 to 42 days). Twenty of 24 patients had cauda equina nerve root enhancement, which was mild in 6 and prominent in 14. Eighteen of 19 with "typical" GBS had enhancement, compared with 2 of 5 with a variant presentation. Sixty percent of patients with prominent enhancement had severe back or leg pain in contrast to 10% of patients with mild or no enhancement. The GBS disability grade (0 to 5 scale) was higher in patients with prominent enhancement, and significantly fewer patients with prominent nerve root enhancement could walk independently by 2 months. There was no relationship between nerve root enhancement and the timing of the MRI, CSF protein, any of several EMG abnormalities, duration of hospitalization, mean disability grade at 2 months, or the time required for patients to improve to grade 2. In two patients, the EMGs at 11 and 20 days, respectively, were normal except for slightly prolonged F-responses and neurogenic recruitment, but there were prominent nerve root enhancement and an elevated CSF protein. Enhancement of the cauda equina nerve roots with gadolinium on lumbosacral MRI is 83% sensitive of acute GBS and was present in 95% of typical cases. This finding may be useful when electrophysiologic abnormalities are equivocal. In addition, conspicuous nerve root enhancement correlates with pain, GBS disability grade, and duration of recovery.

We present three patients with atypical chronic inflammatory demyelinating polyradiculoneuropathy and discuss the management of patients who appear treatment resistant or present with unusual manifestations. The clinical features of the patients included massive nerve root hypertrophy causing myelopathy and movement-provoked paresthesia, pupillary dysfunction, visual loss due to increased intracranial pressure, and focal brachial plexus involvement. Each patient ultimately required prolonged courses of immune modulating therapy before benefit was attained, illustrating the importance of intensive and prolonged treatment combined with objective assessment of response to therapy.

We reviewed the clinical features of 12 patients with neurologic complications following lumbar epidural anesthesia or analgesia. Eleven patients experienced lumbosacral radiculopathy or polyradiculopathy and, of these, 10 received epidural anesthesia or analgesia and one received subarachnoid injection of medication after intended epidural anesthesia. One patient suffered a moderately severe thoracic myelopathy in the setting of unintended spinal anesthesia. The two patients with more severe polyradiculopathy had severe lumbar spinal stenosis on MRI. The other patients experienced mild to moderate neurologic deficits most often involving the L-2 root, and MRIs, when performed, were unremarkable. EMG on three patients helped to localize the lesions to the lumbosacral roots and to quantify the extent of axonal loss. Ten patients were ambulatory upon discharge from the hospital and had good neurologic outcome. One patient with severe polyradiculopathy did not improve after 4 years and had severe motor axonal loss based upon electrodiagnostic studies. The patient with a thoracic myelopathy was ambulatory 4 months after onset. Although generally a safe procedure with low frequency of complications, lumbar epidural anesthesia or analgesia occasionally causes neurologic sequelae such as radiculopathy or myelopathy. Neurologic complications may be more severe in the presence of spinal stenosis or after inadvertent subarachnoid injection of anesthetic or analgesic agent.

We report a case of multifocal demyelinating motor neuropathy in a patient with a 5-year history of progressive, asymmetric, predominantly motor weakness characterized by multifocal progression, multifocal conduction block, and lack of response to steroid therapy. Neuropathologic findings at autopsy showed an "inflammatory demyelinating polyradiculoneuropathy" in the motor cranial nerves and motor roots of peripheral nerves, an extensive deposition of IgG and focal accumulations of IgM in the peripheral nerve motor roots, and loss of motor neurons. These findings clearly document an inflammatory demyelinating polyradiculoneuropathy in multifocal demyelinating motor neuropathy, suggesting a close relation with chronic inflammatory demyelinating polyneuropathy.

We report three patients (two children and one adult) with Guillain-Barré syndrome and magnetic resonance imaging evidence of gadolinium enhancement of the cauda equina and lumbar nerve roots. All three patients exhibited symmetric ascending paralysis and areflexia, and two (one child, one adult) suffered urinary incontinence and retention. Similar enhancement has been observed in patients with chronic inflammatory demyelinating polyneuropathy and suggests proximal nerve inflammation. Magnetic resonance imaging in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy may have diagnostic utility.

AIDS-related polyradiculopathy is a syndrome associated with cytomegalovirus infection. We report two cases of AIDS-related polyradiculopathy in which spinal T1-weighted MRI with gadolinium-DTPA showed enhancement of the pial lining of the conus medullaris, cauda equina, and lumbar nerve roots. Both patients clinically improved with ganciclovir treatment.

Serum and lymphocytes from patients with acute Guillain-Barré polyneuropathy were injected into rat sciatic nerves. Serum from 13 of 17 patients produced perivenular demyelination, associated with lymphocytic infiltration. The pattern of demyelination differed from that caused by experimental allergic neuritis serum. The level of serum demyelinating activity as greatest early in the disease and then decreased. The demyelinating factor was heat-labile but not complement-dependent. Circulating lymphocytes did not cause demyelination in eight patients.

A 34-year-old homosexual man with acquired immune deficiency syndrome developed extraocular muscle deficits, chorioretinitis, and paraplegia without sensory symptoms. EMG showed severe diffuse denervation, but only mildly slowed nerve conduction velocities, in both legs. Meningitis persisted for 6 weeks and was exacerbated prior to the patient's death. Necropsy revealed subpial and subependymal cytomegalovirus (CMV) infection. Histology of ventral roots demonstrated proximal CMV infection and massive fiber loss. In this immunosuppressed patient, CMV caused a severe motor polyradiculopathy by selective destruction of the motor neurons of ventral spinal roots and motor cranial nerves.

We describe five patients with a chronic asymmetric sensorimotor neuropathy most pronounced in the upper extremities with focal involvement of individual nerves. Diagnosis was established by electrophysiologic evidence of persistent multifocal conduction block. Sural nerve biopsy in three patients showed primarily demyelinating-remyelinating changes with varying degrees of fiber loss. Two patients had acute optic neuritis, indicating that the disorder was not always restricted to the peripheral nervous system. Two patients treated with corticosteroids improved, whereas three untreated patients had static deficits or steady progression of symptoms. Chronic multifocal demyelinating neuropathy with persistent conduction block seems to be a variant of chronic acquired demyelinating polyneuropathy and may be immunologically mediated.

The neuropathologic findings are described in a fatal case of Guillain-Barré syndrome with ophthalmoplegia. Demyelination was found in the oculomotor nerves, which were dissected to the terminal branches in the ocular muscles, and in other peripheral nerves. The CNS was intact except for occasional chromatolytic lesions in some motor nerves.

It is unclear whether sporadic reports of concurrent multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) represent coincidence or whether these two demyelinating disorders are pathogenically related. We utilized the sensitivity of magnetic resonance imaging (MRI) in detecting central nervous system (CNS) lesions to investigate 16 patients with CIDP. Six of the 16 had periventricular, subcortical, and brainstem white matter lesions indistinguishable from those seen in MS. Three of these patients had definite clinical and laboratory evidence of MS; three others with abnormal MRIs had no findings indicative of CNS disease. Previous reports have indicated that a significant number of MS patients have peripheral nerve demyelination. Our study suggests that many CIDP patients have concurrent CNS demyelination. Taken together, these observations support the existence of a central-peripheral inflammatory demyelinating syndrome. Whether this combined demyelinating syndrome lies on a spectrum between MS and CIDP or is a separate pathogenic entity will require further investigation.

A patient presented with severe sensory loss and ataxia with total arreflexia, and elevation of CSF protein with pleocytosis. At autopsy there was extensive lymphocytic infiltration of nerves and posterior roots, sparing the anterior roots. Teased fiber preparation of nerve showed a demyelinating lesion. There were no abnormalities in the CNS. The condition appears to be an acute sensory polyneuritis bearing a close relationship to acute Guillain-Barré syndrome.