Peripheral nervous system manifestations of MOG antibody associated disease.

Recent studies have reported the involvement of peripheral nervous system (PNS) in association with MOG-IgG, including isolated neuropathies. In this retrospective study we characterized the PNS involvement in MOG antibody associated disease (MOGAD). Six out of 215 MOGAD patients had PNS involvement (all polyradiculopathy) that occurred concurrently with a CNS demyelinating episode. We also demonstrated MOG expression in healthy human controls' proximal nerve root. Nine patients with true-positive MOG-IgG1 had PNS involvement temporally unrelated to a CNS demyelinating event. All these patients had an alternate etiology of PNS involvement. Isolated peripheral neuropathy is not a feature of MOGAD, but inflammatory nerve root involvement can occur concurrently with CNS demyelinating events.

Nerve Conduction Differences in a Large Clinical Population: The Role of Age and Sex.

BACKGROUND: The normal limits of nerve conduction studies are commonly determined by testing healthy subjects. However, in comprehensive real-life nerve conduction electrodiagnostic (EDX) evaluations, multiple nerves are tested, including normal nerves, for purposes of comparison with abnormal ones. OBJECTIVE: This study aims to evaluate the average values of normal nerve conduction studies in a large population and examined the influence of age and sex. METHODS: EDX parameters were extracted from an electronic database of studies performed from May 2016 to February 2022. Established normal values were used to determine the classification of a nerve study as normal. RESULTS: We identified 10,648 EDX reports with 5077 normally interpreted nerve conduction studies (47.6%) of which 57% (n = 2890) were for females. The median age of studies with no abnormalities was 45.1 years (range < 1 to 92) overall and 42.5 years (range: 0.16 -89.5 years) for males and 47.5 years (range:<1 -91.7) for females. Correlations between age and amplitude, latency, and velocity (p < 0.001) were observed in most nerves. Amplitude correlated negatively with age in adults in all nerves with a mean of -0.44 (range: -0.24 to -0.62). However, in the pediatric population (age < 18 years), amplitude as well as velocity increased significantly with age. In the adult cohort, sex differences were noted, where females had higher mean sensory nerve action potentials in ulnar, median, and radial evaluations (p < 0.001). In older patients (aged > 70 years) with normally interpreted EDX studies (845 records of 528 patients), sural responses were present in 97%. CONCLUSIONS: This real-life study confirms that advanced aging is associated with decreased nerve conduction amplitudes, increased latency, and the slowing of conduction velocity. The findings also indicate higher sensory amplitudes and conduction velocities in females. Sural nerve responses were identified in most adults over age 70.

Population-Based Epidemiology Study of Paraneoplastic Neurologic Syndromes.

OBJECTIVES: Population-based epidemiologic data for paraneoplastic neurologic syndromes (PNSs) in the United States are lacking. Our objective was to evaluate the incidence, prevalence, and associated morbidity of PNS. METHODS: We performed a population-based epidemiology study in Olmsted County, Minnesota, with patients identified between January 1, 1987, and December 31, 2018, using the medical records linkage system of the Rochester Epidemiology Project (REP) who met the definite/probable 2021 PNS criteria and 2004 PNS criteria. Patients with dermatomyositis and myasthenia gravis with underlying tumors were included. Age- and sex-specific population counts were obtained from REP resources for January 1, 2014 (prevalence denominator) and annually for 1987-2018 (incidence denominator). Morbidity was estimated using disability-adjusted life years (DALYs; years lived with disability [YLD] plus years of life lost [YLL]). RESULTS: There were 28 patients with PNS identified (50% female) residing in Olmsted County, Minnesota, with median age at diagnosis of 54.5 (IQR 46.5-69.0) years. All patients had a cancer diagnosis, and 18 (64%) patients were neural autoantibody positive including antineuronal nuclear autoantibody type 1 (ANNA-1/anti-Hu; n = 1), ANNA-2/anti-Ri (n = 1), muscle-type acetylcholine receptor (AChR; n = 6), Purkinje cell cytoplasmic antibody type 1 (PCA-1/anti-Yo; n = 1), kelch-like protein 11 (KLH11; n = 3), collapsin response mediator protein 5 (CRMP-5/anti-CV2; n = 2), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (n = 1), neurofilament light chain (n = 1), leucine zipper 4 (LUZP4; n = 1), and unclassified neural antibodies (n = 1). PNS incidence was 0.6/100,000 person-years and increased over time from 0.4/100,000 person-years (1987-2002) to 0.8/100,000 person-years (2003-2018) (p = 0.06). Prevalence was 5.4/100,000 people. The median follow-up period after PNS diagnosis was 3.1 years (IQR, 1.1-9.9 years). Total disability-adjusted life years (DALYs) for 28 patients with PNS were 472.7 years, based on total years of life lost (YLL) for patients dying between 1987 and 2018 (n = 15) of 445.3 years plus years lived with disability (YLD) 27.4 years. DISCUSSION: PNSs are rare neurologic disorders but are associated with severe morbidity and mortality. The estimated number of prevalent PNS cases in the United States is 17,099, and predicted DALY for all US PNS cases is 292,393 years. Their apparent increasing rate of detection is attributable to increasing physician awareness and availability of serologic testing.

Neurofascin-155 Immunoglobulin Subtypes: Clinicopathologic Associations and Neurologic Outcomes.

BACKGROUND AND OBJECTIVE: Multiple studies highlighting the diagnostic utility of neurofascin-155 (NF155)-immunoglobulin G4 (IgG4) in chronic demyelinating inflammatory polyradiculoneuropathy (CIDP) have been published. However, few studies comprehensively address the long-term outcomes or clinical utility of NF155-immunoglobulin M (IgM) or NF155-immunoglobulin G (IgG) in the absence of NF155-IgG4. We evaluated phenotypic and histopathologic specificity and differences in outcomes between these NF155 antibody isotypes or IgG subclasses. We also compare NF155-IgG4-seropositive cases to other seropositive demyelinating neuropathies. METHODS: Neuropathy patient sera at Mayo Clinic were tested for NF155-IgG4, NF155-IgG, and NF155-IgM autoantibodies. Demographic and clinical data of all seropositive cases were reviewed. RESULTS: We identified 32 NF155 cases (25 NF155-IgG-positive [20 NF155-IgG4-positive], 7 NF155-IgM-seropositive). NF155-IgG4-seropositive patients clinically presented with distal more than proximal muscle weakness, positive sensory symptoms (prickling, asymmetric paresthesia, neuropathic pain), and gait ataxia. Cranial nerve involvement (11/20 [55%]) and papilledema (4/12 [33%]) occurred in many. Electrodiagnostic testing (EDX) demonstrated demyelinating polyradiculoneuropathy (19/20 [95%]). Autonomic involvement occurred in 45% (n = 9, median composite autonomic scoring scale score 3.5, range 1-7). Nerve biopsies from the NF155-IgG4 patients (n = 11) demonstrated grouped segmental demyelination (50%), myelin reduplication (45%), and paranodal swellings (50%). Most patients needed second- and third-line immunosuppression but had favorable long-term outcomes (n = 18). Among 14 patients with serial EDX over 2 years, all except one demonstrated improvement after treatment. NF155-IgG-positive, NF155-IgG4-negative (NF155-IgG-positive) and NF155-IgM-positive patients were phenotypically different from NF155-IgG4-seropositive patients. Sensory ataxia, neuropathic pain, cerebellar dysfunction, and root/plexus MRI abnormalities were significantly more common in NF155-IgG4-positive compared to myelin-associated glycoprotein (MAG)-IgM neuropathy. Chronic immune sensory polyradiculopathy (CISP)/CISP-plus phenotype was more common among contactin-1 neuropathies compared to NF155-IgG4-positive cases. NF155-IgG4-positive cases responded favorably to immunotherapy compared to MAG-IgM-seropositive cases with distal acquired demyelinating symmetric neuropathy (p < 0.001) and had better long-term clinical outcomes compared to contactin-1 IgG (p = 0.04). DISCUSSION: We report long-term follow-up and clinical outcome of NF155-IgG4 cases. NF155-IgG4 but not IgM or IgG cases have unique clinical-electrodiagnostic signature. We demonstrate NF155-IgG4-positive patients, unlike classical CIDP with neuropathic pain and dysautonomia common at presentation. Long-term outcomes were favorable. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that NF155-IgG4-seropositive patients, compared to patients with typical CIDP, present with distal more than proximal muscle weakness, positive sensory symptoms, and gait ataxia.

Paraneoplastic neurological syndrome: an evolving story.

Paraneoplastic neurological syndrome (PNS) comprises a group of neurological disorders that result from a misguided immune response to the nervous system triggered by a distant tumor. These disorders frequently manifest before the diagnosis of the underlying neoplasm. Since the first reported case in 1888 by Oppenheim, the knowledge in this area has evolved rapidly. Several classic PNS have been described, such as limbic encephalitis, paraneoplastic cerebellar degeneration, encephalomyelitis, opsoclonus-myoclonus, sensory neuronopathy, Lambert-Eaton Myasthenic syndrome, and chronic gastrointestinal dysmotility. It is now recognized that PNS can have varied nonclassical manifestations that extend beyond the traditional syndromic descriptions. Multiple onconeural antibodies with high specificity for certain tumor types and neurological phenotypes have been discovered over the past 3 decades. Increasing use of immune checkpoint inhibitors (ICIs) has led to increased recognition of neurologic ICI-related adverse events. Some of these resemble PNS. In this article, we review the clinical, oncologic, and immunopathogenic associations of PNS.

Ranolazine-induced lipid storage myopathy presenting with respiratory failure and head drop.

Ranolazine is an anti-ischemic drug often used along with statins in patients with ischemic heart disease. Ranolazine-induced proximal myopathy or rhabdomyolysis have been rarely reported, but toxic effects of statins could not be completely ruled out in those cases. We report a 68-year-old man with ranolazine-induced myopathy who presented with respiratory insufficiency and head drop. Creatine kinase level was normal. The Patient continued to worsen despite statin cessation but markedly improved after stopping ranolazine. Muscle biopsy showed excessive lipid accumulation predominantly in type 1 myofibers. The precise mechanism of toxicity is not clear. Treating physicians should be aware of this rare but potentially debilitating adverse effect of ranolazine. Prognosis is good upon discontinuation of the offending drug.

Expanding the Spectrum of Chronic Immune Sensory Polyradiculopathy: CISP-Plus.

OBJECTIVE: Sensory loss with normal nerve conduction studies (NCS) from focal sensory root inflammatory demyelination is characteristic of chronic immune sensory polyradiculopathy (CISP). However, nonpure cases involving motor and distal sensory nerves exist (CISP-plus). We hypothesize that CISP-plus and CISP are fundamentally part of the same syndrome through comparison of clinical, neurophysiologic, and pathologic features. METHODS: CISP-plus (primary dorsal root with lesser motor and sensory nerve involvement) and CISP cases were retrospectively analyzed (1986-2019). RESULTS: We identified 44 CISP-plus and 28 CISP cases (n = 72) with 86% (38/44) of patients with CISP-plus and 79% (22/28) of patients with CISP experiencing imbalance. On examination, large fiber sensory loss was present in 98% (43/44) of patients with CISP-plus and 96% (27/28) of patients with CISP. Gait ataxia was evident in 93% (41/44) of patients with CISP-plus and 79% (22/28) of patients with CISP. Mild distal weakness was common in CISP-plus (75%, 33/44). NCS showed mild abnormalities in all patients with CISP-plus and were normal (by definition) in all patients with CISP. Elevated CSF protein, slowing of somatosensory evoked potentials, and MRI root enhancement occurred in most CISP-plus and CISP cases. Eleven CISP-plus nerve biopsies showed loss of large myelinated fibers and onion-bulb formations, most prominent in rootlet biopsies. Immunotherapy resulted in marked improvement of gait ataxia in 84% (27/32) of patients with CISP-plus and 93% (13/14) of patients with CISP with return to normal neurologic examination in half (25/46). CONCLUSION: The recognition of CISP-plus expands the spectrum of CIDP by combining CISP-plus (predominant sensory polyradiculopathy with mild motor and sensory nerve involvement) with pure CISP (focal sensory polyradiculopathy) together as proximal sensory CIDP.

Anti-cN1A antibodies do not correlate with specific clinical, electromyographic, or pathological findings in sporadic inclusion body myositis.

BACKGROUND: Anti-cytosolic 5'-nucleotidase 1A (cN1A) antibodies are commonly detected in patients with sporadic inclusion body myositis (sIBM). However, their pathogenic role has not been established. Moreover, efforts toward identifying sIBM distinct clinicopathologic characteristics associated with these antibodies have yielded conflicting results. METHODS: We first searched for patients, seen in our clinics, tested for anti-cN1A antibodies between December 2015 and December 2019. We identified 92 patients who were diagnosed with sIBM, according to the 2011 ENMC or Griggs et al criteria. Thereafter, we reviewed and compared the clinical and investigational findings of these patients in relation to their antibody status. RESULTS: Anti-cN1A antibodies were present in 47/92 (51%) patients with sIBM. Comparison of seropositive and seronegative cohorts yielded no significant difference in clinical features, including facial weakness, oropharyngeal and respiratory involvement, or disease severity. The antibody titer did not correlate with the clinical phenotype, CK value, or presence of myotonic discharges on EMG. Anti-cN1A antibody positive patients appeared to have more frequent auto-aggressive inflammation on muscle biopsy but not as an isolated myopathological feature. CONCLUSIONS: Our study showed that anti-cN1A antibody positive and negative sIBM patients have similar clinical features and disease severity. Anti-cN1A antibodies in our sIBM cohort did not correlate with any studied clinical or laboratory parameter and, therefore, were of limited value in the patient's assessment.

Improving accuracy of myasthenia gravis autoantibody testing by reflex algorithm.

OBJECTIVE: To improve myasthenia gravis (MG) autoantibody testing. METHODS: MG serologic tests with confirmatory or refuting clinical-electrodiagnostic (EDX) testing and cancer evaluations were reviewed over 4 years (2012-2015). All patients had acetylcholine receptor-binding (AChR-Bi), modulating (AChR-Mo), and striational (STR) autoantibody testing, and negatives reflexed to muscle-specific kinase (MuSK). Thymoma and cancer occurrences were correlated with STR and reflexed glutamic acid decarboxylase 65 (GAD65), ganglionic acetylcholine receptor (α3), collapsin response mediating protein-5, and voltage-gated potassium channel complex autoantibodies. RESULTS: Of 433 samples tested, 133 (31%) met clinical-EDX criteria for MG. Best sensitivity (90%) occurred at AChR-Bi >0.02 nmol/L, leaving 14 negative (6 ocular MG, 7 generalized MG, 1 MuSK MG) with specificity 90% (31 false-positives). Using AChR-Mo antibodies (>20% loss), specificity was better (92%, 24 false-positives), but sensitivity dropped (85%). Specificity improved (95%) by testing AChR-Mo when AChR-Bi are positive, resulting in 45% reduction of false-positives (31-17), maintaining AChR-Bi 90% sensitivity. Cutoff values recommended by area under the curve analysis did not outperform this approach. AChR-Bi and AChR-Mo values were significantly higher in true-positives. CT evaluations in 121 MG samples revealed 16 thymomas. Historical or subsequent cancers occurred in 22. STR and reflexed autoantibodies were not more common in MG with thymoma or other cancers. Full-body CT (n = 34) was performed in those with STR and reflex autoantibody positivity, but without additional cancers found. CONCLUSION: Accuracy of MG serologic testing is improved by reflexing AChR-Bi-positive cases to AChR-Mo. STR and other reflexed cancer evaluation autoantibodies did not provide value beyond standard CT chest imaging at the time of MG diagnosis. Diagnostic certainty is informed by AChR-Bi and AChR-Mo with higher values increasing specificity.

GFAP IgG associated inflammatory polyneuropathy.

BACKGROUND: GFAP (glial fibrillary acidic protein)-IgG is predominantly associated with meningoencephalomyelitis, and neuropathy presentations are rare. METHODS: We reviewed clinical, electrodiagnostic and histopathological presentations of GFAP-IgG associated peripheral neuropathy. RESULTS: We identified six cases, five of whom had peripheral neuropathy as the initial presentation. Acute/subacute polyradicluoneuropathy or proximal nerve involvement was a common presentation. Three had demyelinating neuropathies on electrophysiological studies. Nerve biopsies (n = 2) demonstrated T-cell predominant perivascular inflammatory collections, and all patients with clinical follow up responded favorably to immunotherapy. CONCLUSION: GFAP neuropathy represents a potentially treatable immune-mediated neuropathy and can occur with or without co-existing meningoencephalomyelitis.

Chloroquine and Hydroxychloroquine Myopathy: Clinical Spectrum and Treatment Outcomes.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been associated with muscle toxicity, mostly described as a proximal myopathy with evidence of lysosomal dysfunction on muscle biopsy. In this retrospective study, we aimed to define the clinical phenotype, laboratory features, and treatment outcomes of CQ/HCQ myopathy, as well as the safety profile of these drugs. We identified 13 patients seen between 2000 and 2019, with a median age at presentation of 66 years (range 53-89); 11 were females. At onset of symptoms, patients were on CQ or HCQ for a minimum of 6 months and up to 21 years. Diagnosis was often delayed by a median of 6 months (range 3-48). At presentation, 13 patients reported limb weakness, with five requiring assistance in walking. Ten reported dysphagia, often severe, resulting in marked weight loss or aspiration pneumonia. Nine reported respiratory symptoms, which were multifactorial in four, and four reported severe neck weakness. Myopathy clinical phenotype showed predominant involvement of one or more of the following: proximal limb muscle weakness (12 patients), dysphagia (9), axial weakness (4), and respiratory failure (5). Eleven patients had a cardiac evaluation showing prolonged QT interval in 10 and CQ/HCQ cardiomyopathy (CMP) in four. Ten out of 12 patients markedly improved after discontinuing the medication, but most were left with some residual weakness. Eleven patients had a muscle biopsy showing a myopathy with rimmed vacuoles and marked acid phosphatase reactivity. Nine had elevated creatine kinase level up to 1,199 U/L. Twelve patients had an electromyography (EMG), which showed myopathic motor unit potentials with fibrillation potentials in 11 and myotonic discharges in 3. Higher cumulative dose and longer exposure duration were associated with more severe disability and more common cardiac and swallow involvement, indicating a cumulative dose effect. Herein, we demonstrate that long-term exposure to CQ and HCQ may result in a myopathy with a wide spectrum of clinical presentation and predilection for swallowing, respiratory, and cardiac muscles, often with marked associated morbidity. Once accurately diagnosed and the drug is discontinued, patients usually improve but often fail to return to baseline.

Profile of levodopa-induced dyskinesia in patients of Parkinson's disease: a record based study.

OBJECTIVES: Levodopa-induced dyskinesia (LID) is one of the most disabling complications of long-term pharmacotherapy of Parkinson's disease (PD). The objective of our study was to examine the clinical profile and determinants of severity of LID in Indian PD patients on levodopa therapy. METHODS: Retrospective analysis of records of PD patients with LID was performed. All patients were on levodopa and carbidopa combination. Records of subjects with complete information about disease profile, drug intake, and dyskinesia were analyzed. Characterization of LID was based on responses to part IV of unified Parkinson's disease rating scale (UPDRS). RESULTS: Records of 42 patients (M∶F  =  4·6∶1) were analyzed. The median Hoehn and Yahr (H&Y) stage was 2·5 while median duration of levodopa therapy was 6·16 years (range: 1·91-14·58). Early morning dystonia was reported by 97·6% of the patients. Patients treated with ≧2 concomitant PD medication reported a significantly lower median UPDRS IV A score compared to patients treated with <2 number of concomitant drugs. A trend toward a lower UPDRS IV A score was associated with use of dopamine agonists (DA). Patients with H&Y score ≧3 had a significantly higher median total UPDRS IV A score than patients with H&Y score <3. DISCUSSION: Early morning dystonia might be more common among Indian patients of LID. Use of a higher number of concomitant PD medications alongside levodopa is associated with a reduced severity of dyskinesia, even on prolonged use. Levodopa-induced dyskinesia is not only a drug-related phenomenon but the stage of PD itself also affects the dyskinesia severity.

An update on Spino-cerebellar ataxias.

The dominantly inherited ataxias, also known as Spino-cerebellar ataxias (SCAs), are rapidly expanding entities. New mutations are being identified at remarkable regularity. Recent awareness of molecular abnormalities in SCAs has addressed some of the long sought questions, but gaps in knowledge still exist. Three major categories of SCAs, according to molecular mechanisms, have evolved over recent few years: Polyglutamate expansion ataxia, non-coding zone repeat ataxia, and ataxia due to conventional mutation. Using the fulcrum of these mechanisms, the article provides an update of SCAs. Shared and specific clinical features, genetic abnormalities, and possible links between molecular abnormalities and cerebellar degeneration have been discussed. Emphasis has been placed on the mechanisms of polyglutamate toxicity.

Unusually prominent horizontal gaze palsy in a case of Niemann-Pick type C disease.

Niemann-Pick Type C disease (NPC) is a rare inherited metabolic disorder characterized by lipid accumulation and systemic manifestations due to multiple organ involvement. Only a few cases of NPC have been reported so far from India. Varying presentations and often lack of access to complex diagnostic tests have leaded to initial misdiagnosis on few occasions. We here report a provisionally diagnosed case of NPC with prominent horizontal gaze palsy along with characteristic vertical gaze palsy and normal findings on microscopic examination of skin biopsy specimen.