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INTRODUCTION: There are no validated, practical, and quantitative measures of disease severity in Lambert-Eaton myasthenia (LEM). METHODS: Data from the Effectiveness of 3,4-Diaminopyridine in Lambert-Eaton Myasthenic Syndrome (DAPPER) trial were analyzed to assess triple timed up-and-go (3TUG) reproducibility and relationships between 3TUG times and other measures of LEM severity. RESULTS: The coverage probability technique showed ≥0.90 probability for an acceptable 3TUG difference of ≤0.2, indicating that it is reproducible in LEM patients. The correlation between 3TUG times and lower extremity function scores was significant in subjects who continued and in those who were withdrawn from 3,4-diaminopyridine free base. Worsening patient-reported Weakness Self-Assessment Scale and Investigator Assessment of Treatment Effect scores corresponded with prolongation of 3TUG times. DISCUSSION: The 3TUG is reproducible, demonstrates construct validity for assessment of lower extremity function in LEM patients, and correlates with changes in patient and physician assessments. These findings, along with prior reliability studies, indicate 3TUG is a valid measure of disease severity in LEM.

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Over fifty missense mutations in the gene coding for valosin-containing protein (VCP) are associated with a unique autosomal dominant adult-onset progressive disease associated with combinations of proximo-distal inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). We report the clinical, histological, and molecular findings in four new patients/families carrying novel VCP mutations: c.474 G > A (p.M158I); c.478 G > C (p.A160P); c.383G > C (p.G128A); and c.382G > T (p.G128C). Clinical features included myopathy, PDB, ALS and Parkinson's disease though frontotemporal dementia was not an associated feature in these families. One of the patients was noted to have severe manifestations of PDB and was suspected of having neoplasia. There were wide inter- and intra-familial variations making genotype-phenotype correlations difficult between the novel mutations and frequency or age of onset of IBM, PDB, FTD, ALS and Parkinson's disease. Increasing awareness of the full spectrum of clinical presentations will improve diagnosis of VCP-related diseases and thus proactively manage or prevent associated clinical features such as PDB.

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INTRODUCTION: 3,4-diaminopyridine has been used to treat Lambert-Eaton myasthenia (LEM) for 30 years despite the lack of conclusive evidence of efficacy. METHODS: We conducted a randomized double-blind placebo-controlled withdrawal study in patients with LEM who had been on stable regimens of 3,4-diaminopyridine base (3,4-DAP) for ≥ 3 months. The primary efficacy endpoint was >30% deterioration in triple timed up-and-go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self-assessment of LEM-related weakness (W-SAS). RESULTS: Thirty-two participants were randomized to continuous 3,4-DAP or placebo groups. None of the 14 participants who received continuous 3,4-DAP had > 30% deterioration in 3TUG time versus 72% of the 18 who tapered to placebo (P < 0.0001). W-SAS similarly demonstrated an advantage for continuous treatment over placebo (P < 0.0001). Requirement for rescue and adverse events were more common in the placebo group. DISCUSSION: This trial provides significant evidence of efficacy of 3,4-DAP in the maintenance of strength in LEM. Muscle Nerve 57: 561-568, 2018.

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Myasthenia gravis is a nerve-muscle junction disease, for which the most specific test is an increase in the anti-acetylcholine receptor antibodies (anti-AChR-Abs) titer. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting both upper and lower motor neurons. Positive AChR-Ab in patients with pure ALS are exceedingly rare. We report the case of a patient with confirmed ALS and very high levels of AChR-Ab and review the literature on this topic.

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Objective. To examine the relationship between respiratory functioning and neuropsychological performance, mood, and frontal-lobe-mediated behaviors in ALS patients. Methods. Forty-four patients with probable or definite ALS (El Escorial criteria) completed comprehensive pulmonary and neuropsychological assessments as part of their baseline neurological evaluation. Based on their full vital respiratory capacity, 24 and 20 patients were classified as having impaired or intact respiration, respectively. Results. Comparable demographic characteristics, neuropsychological performance, and self-reported mood symptoms were found between ALS patients with intact versus impaired respiration. However, more respiratory-impaired patients were reported by their caregivers as having clinically significant impairments in frontal-lobe-mediated behaviors. Nevertheless, declines in behavior were evidenced from pre- to post-ALS symptom onset for both respiratory groups, and exploratory analyses revealed greater executive functioning deficits in patients with bulbar versus limb onset as well as respiratory-impaired patients not receiving pulmonary interventions versus those utilizing such interventions at the time of testing. Conclusions. Results suggest that the respiratory insufficiency of ALS patients may potentially produce irreversible deficits in executive functioning; yet once treated, impairments in more basic cognitive abilities may be less evident.

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OBJECTIVE: To compare results of quantitative sudomotor axon reflex testing (QSART), dorsal sural, and sural sensory nerve testing in patients with painful sensory neuropathy (PSN). METHODS: Fifty-six patients with symptoms and neurologic examinations consistent with PSN who had both autonomic and nerve conduction studies were identified from 376 patients with a clinical diagnosis of painful neuropathy. Cases were clinically categorized as large-fiber or small-fiber neuropathies by described criteria. The results of sural, dorsal sural, and QSART tests were then analyzed in relationship to these two clinical groups. RESULTS: Evidence of unmyelinated fiber abnormalities by QSART was noted in 85% of clinical large-fiber and 69% of clinical small-fiber groups. Dorsal sural potentials were absent in all the large-fiber group but also in 52% of clinically classified small-fiber neuropathies. When QSART and dorsal sural abnormalities were combined, the identification of abnormalities in all the cases of PSN was 89% with 75% of cases (42) showing mixed large and small fiber abnormalities, 14% unmyelinated sensory fiber abnormalities (by QSART), and 11% normal studies. CONCLUSION: This study demonstrates the value of combining both QSART and dorsal sural sensory testing in verifying the diagnosis of PSN. The majority of cases demonstrate involvement of unmyelinated C fibers as well as large/medium myelinated fibers, thereby separating mixed large- and small-fiber sensory neuropathies from those cases classified by clinical criteria solely as small-fiber neuropathy.

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Nerve biopsy is often the final step in the diagnostic work-up of neuropathies of unknown origin. The aim of this guideline was to prepare an evidence-based guideline on the methods for performing and evaluating nerve biopsy. The panel performed a search of MEDLINE, hand search of bibliographies of the references retrieved, review of the evidence, and reached agreement by consensus. There were not enough formal studies of diagnostic test accuracy to allow evidence-based recommendations of levels A-C for most questions. The panel summarized the class IV evidence and reached agreement by consensus on the following recommendations: (1) Nerve biopsy should not be performed before adequate clinical, electrophysiological, and laboratory investigation and only be performed with appropriate informed consent. (2) An interactive working relationship with the relevant disciplines involved and the provision of sufficient clinical information is encouraged. (3) Biopsies should be processed and read by professionals with adequate training and experience. (4) Optimal analysis of nerve biopsy is best performed by laboratories that have the facilities and expertise to prepare and evaluate frozen and fixed sections (cryostat, paraffin, and epoxy sections). (5) Immunohistochemistry, teased fiber analysis, electron microscopy, and morphometry may help clarify the diagnosis in some conditions and should be considered as additional studies.

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Our objective was to test the hypothesis that changes in body mass index (BMI) are associated with changes in the clinical course of ALS. We examined the relationships between BMI at first clinical visit and changes in BMI up to a two-year follow-up, and multiple clinical variables related to ALS: age of onset, rate of progression of motor symptoms, and survival. Baseline BMI was classified according to the World Health Organization (WHO) criteria. Changes in BMI were classified as a loss of >1 unit, no change, or a gain of >1 unit. Our results showed that baseline BMI was not associated with age of onset, rate of progression or survival. In contrast, a loss of BMI >1 over two years was associated with significantly shorter survival and a faster rate of progression. In a multiple regression model, these results were independent of gender, site of onset, history of diabetes mellitus and apolipoprotein (ApoE) genotype. In summary, a change in BMI after ALS diagnosis was significantly associated with rate of progression and survival. This raises the possibility that early changes in BMI may identify patients likely to have a more malignant course of the disease. However, further research is needed to clarify the relationship between BMI and ALS.

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Amyotrophic lateral sclerosis (ALS) has been associated with changes in frontal and temporal lobe-mediated cognitive and behavioral functions. Verbal fluency, a sensitive measure to these changes, was utilized to investigate phonemic and semantic abilities in 49 ALS patients and 25 healthy controls (HCs). A subset of the ALS patients was classified as ALS-intact, ALS with mild cognitive impairments (ALS-mild), and ALS with fronto-temporal dementia (ALS-FTD) based on a comprehensive neuropsychological evaluation. Clustering and switching, the underlying component processes of verbal fluency, were analyzed using Troyer's (Troyer, Moscovitch, & Winocur, 1997) and Abwender's (Abwender, Swan, Bowerman, & Connolly, 2001) scoring systems. ALS patients exhibited decreased fluency versus HCs. For phonemic fluency, the intact ALS sample generated fewer clusters and more switches than the ALS-mild and ALS-FTD patients using both scoring systems. This suggests temporal involvement in ALS patients, with increasing frontal lobe involvement in patients with greater cognitive dysfunction. For semantic fluency, similar results were obtained with a greater emphasis on declines in clustering or increased temporal lobe dysfunction. These results suggest that verbal fluency measures identify frontal and temporal lobe involvement in the cognitive decline associated with ALS, particularly when the component processes are evaluated. The clinical utility of these scoring systems with ALS patients is also discussed.

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Prominent acral mutilating ulcers can be present in sensorimotor neuropathies. Although diabetes mellitus is the most common cause of neuropathic ulcers, these skin lesions may manifest in nondiabetic neuropathies. The dermatologic abnormalities may even precede the onset of typical neuropathic symptoms, leading to diagnostic confusion. Therefore, a broad differential diagnosis of neurological and systemic disorders should be considered when evaluating patients who have acral skin ulcerations. We report 3 cases of mutilating ulcers associated with nondiabetic neuropathies. The first case is a woman with multiple ulcerations on her forearm, hands, and toes. Her nerve biopsy revealed neuropathy with multiple congophilic deposits consistent with amyloid neuropathy. The second case is a woman with necrotic painless ulcer on her heel. Nerve biopsy in this patient revealed features suggestive of vasculitic neuropathy. The third case is a man with multiple ulcers on his extremities. A sural nerve biopsy in this patient was consistent with leprous neuropathy.

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VAP proteins (human VAPB/ALS8, Drosophila VAP33, and C. elegans VPR-1) are homologous proteins with an amino-terminal major sperm protein (MSP) domain and a transmembrane domain. The MSP domain is named for its similarity to the C. elegans MSP protein, a sperm-derived hormone that binds to the Eph receptor and induces oocyte maturation. A point mutation (P56S) in the MSP domain of human VAPB is associated with Amyotrophic lateral sclerosis (ALS), but the mechanisms underlying the pathogenesis are poorly understood. Here we show that the MSP domains of VAP proteins are cleaved and secreted ligands for Eph receptors. The P58S mutation in VAP33 leads to a failure to secrete the MSP domain as well as ubiquitination, accumulation of inclusions in the endoplasmic reticulum, and an unfolded protein response. We propose that VAP MSP domains are secreted and act as diffusible hormones for Eph receptors. This work provides insight into mechanisms that may impact the pathogenesis of ALS.

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Diabetic neuropathies are the most common types of neuropathies worldwide. Although there has been significant progress in the understanding of the clinical aspects of these conditions, many questions remain unanswered or difficult to answer in terms of causation, risk factors and genetic susceptibility, effective treatments and restoration of nerve functions, and pain management. The major handicap in studying diabetic neuropathies is the lack of a suitable animal model that addresses acute and chronic events leasing to diabetic neuropathy. Unfortunately and despite numerous drug trials, other than strict glycemic control, which is often difficult to maintain, there are no other treatments to slow the progression or delay the development of diabetic neuropathy. This article attempts to highlight a few unanswered or controversial questions regarding diabetic neuropathies.

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Spinal epidural lipomatosis (SEL) is accumulation of unencapsulated fat tissue within the epidural space of the spinal canal. The most common cause of SEL is corticosteroid therapy, whereas most of the non-corticosteroid-dependent cases are idiopathic. If unrecognized, it may result in diagnostic confusion with other neuropathic or myelopathic conditions. We report 2 cases of SEL. The first case is of a 30-year-old man who received corticosteroid therapy for an acute and probably immune-mediated demyelinating process. Subsequently, the addition of compressive effects of SEL resulted in diagnostic confusion and initial workup at other centers for spinal cord malignancy and vascular malformation. The patient's symptoms improved after decompression surgery. The second case is of a 63-year-old woman with a history of type 1 diabetes mellitus that presented with increasing numbness in the lower extremities. She was initially diagnosed with diabetic neuropathy; however, the presence of myelopathic signs led to further investigation and diagnosis of SEL. Decompression surgery resulted in improvement of symptoms.

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West Nile virus is a mosquito-borne RNA Flavivirus infection transmitted to humans and other vertebrates, mainly by the Culex species of mosquito. Since the mid-1990s, the frequency and apparent clinical severity of West Nile virus outbreaks have increased. We report the case of a patient who developed West Nile virus encephalitis shortly after undergoing cardiac transplantation. Clinicians should be aware of the possibility of West Nile virus infection in transplant recipients and in patients receiving blood transfusions.

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BACKGROUND: The mendelian forms of progressive external ophthalmoplegia (PEO) associated with multiple mitochondrial DNA deletions are clinically heterogeneous disorders transmitted as dominant or recessive traits. Autosomal dominant PEO is caused by mutations in at least 3 genes: adenine nucleotide translocator-1 (ANT1), encoding the muscle-specific adenine nucleotide translocator; chromosome 10 open reading frame 2 (C10orf2), encoding Twinkle helicase; and polymerase gamma (POLG), encoding the alpha subunit of polymerase gamma. Mutations in POLG can also cause autosomal recessive PEO, which is often associated with multisystemic disorders. OBJECTIVE AND METHODS: To further investigate the frequency and genotype-phenotype correlations of mutations in the POLG gene, we used single-stranded conformational polymorphism analysis and direct sequencing to screen 30 patients with familial or sporadic PEO and multiple mitochondrial DNA deletions in muscle but without mutations in ANT1 and C10orf2. RESULTS: Four unrelated patients had novel POLG mutations. A woman with PEO and mental retardation had a heterozygous Gly1076Val mutation. Two patients, one with PEO, exercise intolerance, and gastrointestinal dysmotility and the other with PEO, neuropathy, deafness, and hypogonadism, both had a Pro587Leu change. The fourth patient, who was compound heterozygous for Ala889Thr and Arg579Trp mutations, had PEO, gastrointestinal dysmotility, and neuropathy. These mutations were not detected in 120 healthy control alleles. CONCLUSIONS: Our results demonstrate that POLG mutations account for a substantial proportion of patients (13%) with PEO and multiple mitochondrial DNA deletions and cause both clinically and genetically heterogeneous disorders.

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OBJECTIVE: Since the discovery of mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) ten years ago, testing for SOD1 gene mutations has become a part of the investigation of patients with suspected motor neuron disease. We searched for novel SOD1 mutations and for clinical characteristics of patients with these mutations. METHODS: Analysis was made of patient files at the Neurogenetic DNA Diagnostic Laboratory at Massachusetts General Hospital. We also scrutinized available medical records and examined patients with the different SOD1 mutations. RESULTS: One hundred and forty eight (148) of 2045 amyotrophic lateral sclerosis (ALS) patients carried a disease-associated mutation in the SOD1 gene. The most prevalent was the A4V missense mutation, found in 41% of those patients. Sixteen novel exonic mutations (L8V, F20C, Q22L, H48R, T54R, S591, V87A, T88deltaTAD, A89T, V97M, S105deltaSL, V118L, D124G, G141X, G147R, 11515) were found, bringing the total number of SOD1 gene mutations in ALS to 105. CONCLUSIONS: Mutations in the SOD1 gene are found both in sporadic and familial ALS cases without any definite predilection for any part of the gene. A common structural denominator for the 16 novel mutations or previously reported mutations is not obvious. Similarly, the nature of the putative acquired toxic function of mutant SOD1 remains unresolved. We conclude that patients with SOD1 mutations may infrequently show symptoms and signs unrelated to the motor systems, sometimes obscuring the diagnosis of ALS.

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