OBJECTIVE:To describe the clinical and pathologic features of patients and their peripheral nerve biopsies in cases of breast cancer with perineurial invasion of the brachial plexus. BACKGROUND:Tumor spread to peripheral nerves usually portends a poorer prognosis. Identification of such cases can have significant implications on management, outcomes, and patient counseling. While the clinical features in such patients have been previously described, there is a paucity of information on the pathologic features. We sought to review the microscopic findings on nerve biopsies in patients with breast cancer spread to the brachial plexus. DESIGN/METHODS:Review of the clinical, radiologic, and pathologic features of patients with brachial plexus perineurial invasion from metastatic breast carcinoma. RESULTS:We found 19 patients with brachial plexus invasion from breast cancer who underwent nerve biopsies. Symptoms were on the left in twelve and on the right in seven. The most common initial neurologic symptom was pain (9/19). At presentation, all patients had pain and weakness, and 16 patients reported numbness. Panplexopathy was the most common pattern. Physical exam, electrodiagnostic studies, and imaging guided selection of fascicular biopsy site within the brachial plexus. Two patients did not have tumor involvement on nerve biopsy. The most common findings were generalized myelinated fiber loss (15/19), endoneurial inflammation (17/19), perineurial inflammation (10/19), and tumor preferentially involving the perineurium (8/17) or subperineurium (4/17). At average follow-up time of 4 years, 16 patients had passed away after an average of 20 months from diagnosis of brachial plexus invasion. CONCLUSIONS:Pain and weakness in a panplexopathy pattern are common in patients with brachial plexus invasion by breast adenocarcinoma. Nerve biopsies demonstrate tumor invasion predominantly in the perineurium/subperineurium, and inflammatory cells within the endoneurium and perineurium. We suspect that the tumor spreads within the nerve primarily via the perineurium/subperineurium, and the presence of the neoplasm induces an inflammatory response. Disclosure: Dr. Granger has nothing to disclose. Dr. Lamb has received research support from Immunovant, Inc. Dr. Dyck has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea/Ionis.

Objective: To describe clinical and pathological features of a rare immune myopathy featured by regional ischemia in the setting of cancer. Background: Regional ischemic immune myopathy (RIIM) is a rare disorder attributed to myovasculopathy and considered paraneoplastic. It has a high mortality rate. Contrary to dermatomyositis, where microvasculopathy leads to perifascicular pathology and sometimes muscle ischemia, RIIM is characterized by regional necrosis in border zones between perimysial vessels. Design/Methods: Review of patient's clinical and laboratory findings. Results: An 81-year-old man manifested subacute proximal limb weakness, dysphagia, and 25-pound weight loss. He had stage IV prostate cancer, diagnosed 3 months prior to weakness-onset. Examination revealed mild facial weakness, flaccid dysarthria, moderate-to-severe neck and limb girdle weakness and atrophy. Videofluoroscopic swallow study showed severe oropharyngeal dysphagia with aspiration. CK was 689 U/L (normal 39–108 U/L) at presentation but 6,145 U/L six weeks earlier. Myositis-associated and HMGCR antibodies were negative. EMG showed proximal-predominant myopathic changes with fibrillation potentials. Muscle biopsy revealed several well-demarcated areas of ischemia involving adjacent fascicles. Necrotic fibers were in a similar early stage of necrosis with no macrophagic infiltration and diffuse sarcoplasmic C5b-9 deposition. A few small collections of perimysial perivascular inflammatory cells were present in the areas of the specimen not affected by ischemia. There was patchy capillary depletion and dilation; some capillaries in areas not affected by ischemia showed complement deposition. Myxovirus resistance protein A (MxA) expression occurred diffusely, especially in necrotic fibers, but without perifascicular predominance. Patient received IVIG 2g/Kg and prednisone 40 mg daily. The limb weakness stabilized while the dysphagia progressed. He expired 3 weeks later. Conclusions: RIIM is a rare myovasculopathy leading to muscle weakness in the setting of cancer. In keeping with published data, it has a poor prognosis. The identification of RIIM myopathological changes should trigger the search for underlying malignancy in patients without known cancer. Disclosure: Dr. Granger has nothing to disclose. Dr. Soontrapa has nothing to disclose. Dr. Klein has a non-compensated relationship as a Klein with Neurology Journal that is relevant to AAN interests or activities. Dr. Milone has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Milone has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics, AAN. The institution of Dr. Milone has received research support from Mayo Clinic, CCaTS-CBD. The institution of Dr. Milone has received research support from Mayo Clinic, SGP Award. The institution of Dr. Milone has received research support from MDA for Care Center grant. The institution of Dr. Milone has received research support from Regenerative medicine Minnesota.

Background and Objectives Pathologic descriptions of peripheral nerve involvement in paraneoplastic neuropathies are sparse, mostly from autopsies focusing on CNS and dorsal root ganglia tissues. Here, we describe the clinicopathologic features of peripheral nerve biopsies in patients with paraneoplastic neurologic syndromes to expand the currently limited knowledge. Methods Retrospective review of the Mayo Clinic electronic medical record from 1995 to 2022 for patients identified to have subacute onset neuropathy with paraneoplastic antibodies identified in our neuroimmunology laboratory having available nerve biopsies performed at the time of diagnosis. Patients with another cause of neuropathy not linked to their subacute onset were excluded. Results Nineteen patients met inclusion criteria: 4 with amphiphysin antibodies, 6 with antineuronal nuclear antibody (ANNA)-1 only, 3 with both ANNA-1 and collapsin response-mediator protein 5 (CRMP-5), 2 with ANNA-2, and 4 with CRMP-5 antibodies only. Fifteen biopsies had reduced the density of myelinated nerve fibers—4 with multifocality. Subperineurial edema was present in 17 biopsies. Prominent epineurial perivascular inflammation was present in 3 biopsies, all belonging to patients with a lumbosacral radiculoplexus neuropathy (LRPN) phenotype. Discussion Axonal loss, subperineurial edema, and an absence of prominent inflammation are the most common findings in nerve biopsies of patients with paraneoplastic antibodies strongly associated with cancer. The LRPN phenotype was the only subset with inflammatory collections. Paraneoplastic autoantibody testing should be considered in patients with subacute onset neuropathies, with or without interstitial inflammatory findings.

A rare disorder in the USA is one that affects <200,000 people, making inherited myopathies rare diseases. Increasing access to genetic testing has been instrumental for the diagnosis of inherited myopathies. Genetic findings, however, require clinical correlation due to variable phenotype, polygenic etiology of certain inherited disorders, and possible co-existing independent neuromuscular disorders. We searched the Mayo Clinic Rochester medical record (2004-2020) to identify adult patients carrying pathogenic variants or likely pathogenic variants in genes causative of myopathies and having a coexisting independent neuromuscular disorder classified as rare at https://rarediseases.info.nih.gov/. One additional patient was identified at Nationwide Children's hospital. Clinical and laboratory findings were reviewed. We identified 14 patients from 13 families fulfilling search criteria. Seven patients had a "double-trouble" inherited myopathy; two had an inherited myopathy with coexistent idiopathic myositis; three had an inherited myopathy with coexisting rare neuromuscular disorder of neurogenic type; a female DMD carrier had co-existing distal spinal muscular atrophy, which was featuring the clinical phenotype; and a patient with a MYH7 pathogenic variant had Sandhoff disease causing motor neuron disease. These cases highlight the relevance of correlating genetic findings, even when diagnostic, with clinical features, to allow precise diagnosis, optimal care, and accurate prognosis.

Objective: To describe peripheral nerve histopathology in neuropathy patients with paraneoplastic neurological syndromes (PNS) supported by autoantibody testing. Background: Rare autopsy cases in PNS suggest an association with shared antigens of misdirected cytotoxic T-cells against cancers and neural tissues. Neuropathy may be the first manifestation but reports of peripheral nerve pathology are limited. We sought to review the pathologic findings within nerve biopsies of patients having neuropathies linked to cancer and high-risk paraneoplastic antibody seropositivity. Design/Methods: We retrospectively reviewed the clinical data and nerve biopsy reports of patients presenting with neuropathy and paraneoplastic syndromes reviewing their cancer diagnosis and peripheral onsets. Results: Twelve sural nerves and one radial nerve were biopsied from patients with the following antibodies: Amphiphysin (n=6); Antineuronal nuclear antibodies (ANNA)-1 (n=2); ANNA-2 (n=2); Collapsin response mediator protein-5 (CRMP-5) (n=2); and Purkinje cytoplasmic antibody (PCA1) (n=1). Antibody testing occurred typically after biopsy or concurrently, and all patients had subacute onsets. Patients had overlapping involvements: length-dependent neuropathies (n=5), cranial neuropathies (n=1), brachial plexopathy (n=1), multiple mononeuropathies (n=2), and lumbosacral radiculoplexus involvement (n=8). Time to diagnosis was prolonged; commonly after one year. Malignancies were diverse including breast, ovarian, bladder, non-small cell lung cancer, small cell lung cancer, and coexisting colon and breast cancer. Fiber density was reduced in all, with multifocality frequently seen. Perineurial injury was absent, but sub-perineurial edema was common (n=4). Significant inflammation was absent in all but 5 cases, where small to moderate-sized CD45 collections were seen with vessel wall involvement with clinical lumbosacral plexus neuropathy (Amphiphysin (n=2), ANNA-2, and CRMP5) or multiple mononeuropathies (PCA-1). Conclusions: The absence of inflammatory infiltrates with reduced fiber density in distal sensory nerve biopsies is common in paraneoplastic neuropathies. A proximal inflammatory process is theorized. Microvessel inflammatory infiltrates with vessel wall involvement also occurs especially among lumbosacral plexopathy phenotypes. Disclosure: Dr. Granger has nothing to disclose. Dr. Rajnauth has nothing to disclose. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. The institution of Dr. Dubey has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Astellas. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argenx. Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for AGRIMS. Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Advances in Neurology . Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Moffit Cancer Center . Dr. Dubey has received research support from Department of Defense . Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Mills has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Mauermann has received research support from IONIS. The institution of Dr. Mauermann has received research support from Alnylam. Dr. Mauermann has received publishing royalties from a publication relating to health care. Dr. Berini has nothing to disclose. Dr. Dyck has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea/Ionis. Dr. Klein has a non-compensated relationship as a Klein with Neurology Journal that is relevant to AAN interests or activities.

To describe atypical myopathological findings in 2 patients with GNE myopathy.

Granger, Andre MD, MBA; Sorenson, Eric J. MD; Selcen, Duygu MD; Liewluck, Teerin MD Author Information

Patient 1, a 23-year-old male, and patient 2, a 28-year-old female, developed progressive painless footdrop at age 18 and 20 years, respectively. The weakness progressed to involve distal upper limb and proximal muscles. Neurologic examination showed generalized limb weakness, most severely affecting tibialis anterior. Creatine kinase levels were mildly elevated. Needle electromyography detected myopathic motor unit potentials and frequent fibrillation potentials. Muscle biopsy revealed several fibers harboring rimmed vacuoles and a few fibers containing non-rimmed vacuoles filled with periodic acid-Schiff-positive, diastase-labile material, consistent with glycogen (Fig. 1).

Inflammatory peripheral neuropathies can be disabling for any patient. Selecting the most appropriate agent for treatment, especially in the elderly, is no simple task. Several factors should be considered. Herein, we discuss immunotherapeutic options for peripheral nerve diseases and the important considerations required for choosing one in the geriatric population.

Toxic metabolic encephalopathy (TME) has been reported in 7–31% of hospitalized patients with coronavirus disease 2019 (COVID-19); however, some reports include sedation-related delirium and few data exist on the etiology of TME. We aimed to identify the prevalence, etiologies, and mortality rates associated with TME in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients. We conducted a retrospective, multicenter, observational cohort study among patients with reverse transcriptase–polymerase chain reaction-confirmed SARS-CoV-2 infection hospitalized at four New York City hospitals in the same health network between March 1, 2020, and May 20, 2020. TME was diagnosed in patients with altered mental status off sedation or after an adequate sedation washout. Patients with structural brain disease, seizures, or primary neurological diagnoses were excluded. The coprimary outcomes were the prevalence of TME stratified by etiology and in-hospital mortality (excluding comfort care only patients) assessed by using a multivariable time-dependent Cox proportional hazards models with adjustment for age, race, sex, intubation, intensive care unit requirement, Sequential Organ Failure Assessment scores, hospital location, and date of admission. Among 4491 patients with COVID-19, 559 (12%) were diagnosed with TME, of whom 435 of 559 (78%) developed encephalopathy immediately prior to hospital admission. The most common etiologies were septic encephalopathy (n = 247 of 559 [62%]), hypoxic-ischemic encephalopathy (HIE) (n = 331 of 559 [59%]), and uremia (n = 156 of 559 [28%]). Multiple etiologies were present in 435 (78%) patients. Compared with those without TME (n = 3932), patients with TME were older (76 vs. 62 years), had dementia (27% vs. 3%) or psychiatric history (20% vs. 10%), were more often intubated (37% vs. 20%), had a longer hospital length of stay (7.9 vs. 6.0 days), and were less often discharged home (25% vs. 66% [all P < 0.001]). Excluding comfort care patients (n = 267 of 4491 [6%]) and after adjustment for confounders, TME remained associated with increased risk of in-hospital death (n = 128 of 425 [30%] patients with TME died, compared with n = 600 of 3799 [16%] patients without TME; adjusted hazard ratio [aHR] 1.24, 95% confidence interval [CI] 1.02–1.52, P = 0.031), and TME due to hypoxemia conferred the highest risk (n = 97 of 233 [42%] patients with HIE died, compared with n = 631 of 3991 [16%] patients without HIE; aHR 1.56, 95% CI 1.21–2.00, P = 0.001). TME occurred in one in eight hospitalized patients with COVID-19, was typically multifactorial, and was most often due to hypoxemia, sepsis, and uremia. After we adjustment for confounding factors, TME was associated with a 24% increased risk of in-hospital mortality.

We appreciate the comments by Kumar et al. on our article.1 The referenced Kremer study2 was a retrospective case series and included patients with positive MRI findings only. It is unclear whether the patients with the diagnosis of "encephalitis" met diagnostic or causal criteria outlined by the International Encephalitis Consortium3 and others.4 Indeed, CSF SARS-CoV-2 RT-PCR was negative in 20 patients. In 2 of 3 with CSF pleocytosis (>5 cell/mm3), imaging was performed >2 weeks from symptom onset, possibly representing postinfectious autoimmune encephalitis and not infectious encephalitis. Many of the MRI findings described are nonspecific and can be seen in hypoxic/ischemic brain injury, metabolic encephalopathy, or postseizure. Notably, 100% of "encephalitis" patients required oxygen and 75% had ARDS, suggesting that a proportion of the MRI changes may represent hypoxic/ischemic injury (defined as a global insult due to hypoxemia, hypotension, or cardiac arrest). Although we detected elevated CSF protein in some patients,1 this is nonspecific and can be found in stroke, hemorrhage (or traumatic tap), hypoxic/ischemic injury, diabetes, uremia, tumor, neuropathy, and many other conditions. Because the implications of SARS-CoV-2 neurotropism are far reaching, we believe that it is critical to follow the most rigorous standards and criteria when ascribing encephalitis/meningitis/myelitis to SARS-CoV-2 infection.

Granger, Andre MD, MBA; Omari, Mirza MD, MPH; Jakubowska-Sadowska, Katarzyna MD; Boffa, Michael MD; Zakin, Elina MD Author Information

The inferior petrosal sinus (IPS) occupies an important position at the skull base and must be considered with surgical approaches to this area. Moreover, more recent, minimally invasive intravascular procedures necessitate sampling blood from this sinus. Therefore, detailed knowledge of its anatomy and variations is important in clinical practice. This chapter focuses on the anatomy and clinical aspects of the IPS.

Saturday, April 25April 14, 2020Free AccessGrave’s Disease Mimicking a Structural Myelopathy (5100)Andre Granger and Arielle KurzweilAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.5100 Letters to the Editor

A 38-year-old male presented with a three-week history of bilateral lower extremity choreiform movements. History included sleep abnormalities, rushed and unintelligible speech, with delusions two to six months prior to presentation. He also developed mild dysphagia, staring spells, and anterograde amnesia. On examination, he had pressured speech, asynchronous cycling movements of the bilateral lower extremities persisting during sleep, occasional ballistic movements of the upper extremities, and ataxia. Magnetic resonance imaging (MRI) of the brain showed high cortical signal change in bilateral parieto-occipital cortices with evidence of medullary olive hypertrophy bilaterally. Electroencephalography showed generalized slowing without periodic spikes. Cerebrospinal fluid was positive for protein 14-3-3 and real-time quaking-induced conversion. Genetic testing was positive for autosomal dominant prion protein gene (PRNP) genetic mutation. The patient passed away three months after discharge. This case provides previously undescribed imaging and movement abnormalities in a patient with familial Creutzfeldt-Jakob disease (CJD), and suggests that CJD should not be removed from the differential in patients with these atypical findings.

Objective: To investigate the effect of SARS-CoV-2 infection on patients with myasthenia gravis. Background: Myasthenic crisis is most commonly precipitated by infection and carries a mortality rate of about 4%. In patients with respiratory failure secondary to infection with the SARS-CoV-2, the mortality rate is estimated to be between 10–24%. The effect that COVID-19 has on patients with myasthenia gravis and the characteristics that affect outcome require further investigation. Design/Methods: Retrospective analysis of seven patients with Myasthenia Gravis infected with SARS-CoV-2. Results: Of the seven patients with myasthenia gravis, baseline neurologic exam, comorbidities (diabetes, age, BMI) and medication regimen prior to infection with SARS-CoV-2 did not clearly appear to affect the probability of requiring admission or mortality. Five of the seven patients required hospitalization, with two eventually expiring. Both patients who expired had the longest disease duration of the group (mean = 9 years), with respiratory failure as the cause of clinical decompensation. Higher inflammatory markers (i.e. ESR, CRP, D-dimer) were found on serologic studies of those two patients, with marked increases in ferritin and D-dimer levels. Lower absolute lymphocyte count appears to be associated with worse clinical outcome. Of note, two of the five hospitalized patients received a dose of a monoclonal antibody against interleukin-6 (i.e. tocilizumab) and had marked improvement in their clinical course, ultimately discharged at their baseline neurologic status. Conclusions: These patients appear to share some of the typical risk factors for poor outcomes in patients with myasthenic crises without SARS-CoV-2 infection. The management of immunosuppression in this patient population is challenging, but a benefit of immunosuppression is suggested. Further larger scale investigations to delineate specific guidelines and establish factors that affect clinical outcomes in this specific patient population is warranted. Disclosure: Dr. Granger has nothing to disclose. Dr. Kwon has nothing to disclose. Dr. Zakin has nothing to disclose.

The torcular Herophili (confluence of sinuses) is a highly variable structure that constitutes a vital part of the network of dural venous sinuses. The torcular Herophili is defined historically as the intersection of the superior sagittal sinus, the straight sinus, the occipital sinus, and the two transverse sinuses. Its size varies and it is located inferior to the occipital lobes and posterosuperiomedially to the cerebellum. This chapter outlines the anatomy and clinical implications of this sinus.