Sports and trauma as risk factors for Motor Neurone Disease: New Zealand case-control study.

OBJECTIVES: To assess whether sports, physical trauma and emotional trauma are associated with motor neurone disease (MND) in a New Zealand case-control study (2013-2016). METHODS: In total, 321 MND cases and 605 population controls were interviewed collecting information on lifetime histories of playing sports, physical trauma (head injury with concussion, spine injury) and emotional trauma (14 categories). ORs were estimated using logistic regression adjusting for age, sex, ethnicity, socioeconomic status, education, smoking status, alcohol consumption and mutually adjusting for all other exposures. RESULTS: Head injury with concussion ≥3 years before diagnosis was associated with MND (OR 1.51, 95% CI: 1.09-2.09), with strongest associations for two (OR 4.01, 95% CI: 1.82-8.86), and three or more (OR 2.34, 95% CI: 1.00-5.45) head injuries. Spine injury was not associated with MND (OR 0.81, 95% CI: 0.48-1.36). Compared to never playing sports, engaging in sports throughout childhood and adulthood increased MND risk (OR 1.81, 95% CI: 1.01-3.25), as was more than 12 years playing football/soccer (OR 2.35, 95% CI: 1.19-4.65). Reporting emotionally traumatic events in more than three categories was associated with MND (OR 1.88, 95% CI: 1.17-3.03), with physical childhood abuse the only specific emotional trauma associated with MND (OR 1.82, 95% CI: 1.14-2.90), particularly for those reporting longer abuse duration (OR(5-8 years) 2.26, 95% CI: 1.14-4.49; OR(>8 years) 3.01, 95% CI: 1.18-7.70). For females, having witnessed another person being killed, seriously injured or assaulted also increased MND risk (OR 2.68, 95% CI: 1.06-6.76). CONCLUSIONS: This study adds to the evidence that repeated head injury with concussion, playing sports in general, and playing football (soccer) in particular, are associated with an increased risk of MND. Emotional trauma, that is physical abuse in childhood, may also play a role.

Tat-p27 Ameliorates Neuronal Damage Reducing α-Synuclein and Inflammatory Responses in Motor Neurons After Spinal Cord Ischemia.

p27Kip1 (p27) regulates the cell cycle by inhibiting G1 progression in cells. Several studies have shown conflicting results on the effects of p27 against cell death in various insults. In the present study, we examined the neuroprotective effects of p27 against H2O2-induced oxidative stress in NSC34 cells and against spinal cord ischemia-induced neuronal damage in rabbits. To promote delivery into NSC34 cells and motor neurons in the spinal cord, Tat-p27 fusion protein and its control protein (Control-p27) were synthesized with or without Tat peptide, respectively. Tat-p27, but not Control-27, was efficiently introduced into NSC34 cells in a concentration- and time-dependent manner, and the protein was detected in the cytoplasm. Tat-p27 showed neuroprotective effects against oxidative stress induced by H2O2 treatment and reduced the formation of reactive oxygen species, DNA fragmentation, and lipid peroxidation in NSC34 cells. Tat-p27, but not Control-p27, ameliorated ischemia-induced neurological deficits and cell damage in the rabbit spinal cord. In addition, Tat-p27 treatment reduced the expression of α-synuclein, activation of microglia, and release of pro-inflammatory cytokines such as interleukin-1ß and tumor necrosis factor-α in the spinal cord. Taken together, these results suggest that Tat-p27 inhibits neuronal damage by decreasing oxidative stress, α-synuclein expression, and inflammatory responses after ischemia.

Cancer and motor neuron disease-causal or coincidental? Two contrasting cases.

INTRODUCTION: Motor neuron disease (MND) can occur in patients with cancer, but there is minimal evidence that this is more than by chance. We contrast two cases of motor neuronopathies occurring in the context of systemic malignancy and argue that in one case the cause was most likely paraneoplastic, while in the other it was not. CASE 1: A 61-year-old woman developed progressive walking difficulties over 9 months with weakness and stiffness in her legs. EMG showed fibrillations and positive sharp waves in multiple lower limb muscles bilaterally, with neurogenic units and a reduced recruitment pattern. An invasive ductal carcinoma of the breast was identified and she continued to deteriorate neurologically with worsening mobility, upper limb spasticity and fasciculations. She died approximately 26 months after symptom onset. CASE 2: A 57-year-old woman developed weight loss and weakness of her right arm without any sensory symptoms. At presentation, she had wasting and fasciculations in her right upper limb muscles, with normal reflexes, normal left upper limb and lower limb examination. Over the following week, she developed left upper limb weakness and fasciculations, brisk knee reflexes, and flexor plantar responses. Her EMG showed upper and lower limb denervation. She was found to have anti-Hu and anti-CV2 antibodies present in serum. A PET-CT showed active uptake in lymph nodes in the right hilum. Biopsy confirmed a small cell lung cancer. She had chemoradiation therapy and the tumour went into remission. She has remained well on follow-up 24 months later, regaining weight and strength after her chemotherapy. She continues to be monitored for cancer recurrence, but thus far appears to be in remission. CONCLUSION: In cases with rapidly progressive MND, particularly of upper limb onset, consideration should be given to testing anti-neuronal antibodies and searching for an occult tumour.

Autopsy-proven case of paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia.

We report a case of a male patient with a 19-year history of monoclonal and later polyclonal gammopathy who subsequently developed tetraparesis, bulbar palsy, and respiratory failure. Autopsy findings showed degeneration of the hypoglossal nuclei, prominent neuronal loss and atrophy in the anterior horn of the whole spinal cord despite the presence of mild astrocytosis, degeneration of the gracilis on one side, and infiltration of inflammatory cells, which included B cells and plasma cells in the anterior and posterior roots of the lumbar spinal cord, iliopsoas muscle, and perivascular area of the cervical cord. On immunostaining, cytoplasmic inclusions of phosphorylated transactivation response DNA-binding protein of 43 kDa were observed in the motor neurons and astrocytes of the hypoglossal nuclei and whole spinal cord. The final diagnosis was paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia.

Motor neuron disease of paraneoplastic origin: a rare but treatable condition.

Paraneoplastic motor neuron disorders (MND) are rare conditions; their exact clinical and electrophysiological phenotype have not been exhaustively described yet. The purpose of this study is to depict the main characteristics of paraneoplastic MND to highlight the features that may allow its diagnosis. Based on the description of eight original cases, and on the revision of 21 patients identified from a systematic review of the literature, the main features of paraneoplastic MND can be summarized as follows: (1) subacute; (2) lower motor neuron syndrome, associated or not with upper motor neuron involvement; (3) predominant asymmetric upper limb involvement; (4) presence of other non-motor neurological manifestations, including sensory neuronopathy; (5) signs of inflammation in the cerebrospinal fluid (CSF); (6) neurological improvement or stabilization after immunotherapy and tumor treatment. The diagnosis of paraneoplastic MND may be difficult because of its rarity, the absence of pathognomonic clinical features, and the frequent absence of prior tumor history. However, it is of capital importance to correctly identify patients with paraneoplastic MND, as this represents a potentially treatable condition. In the presence of subacute lower motor neuron impairment, especially when atypical clinical features for degenerative MND or other non-motor neurological manifestations are present, we recommend testing for onconeural antibodies. In the case, the search for onconeural antibodies is negative, but it exists a strong clinical suspicion for a paraneoplastic etiology; CSF analysis and total-body 18FDG-PET/CT imaging should be performed to circumstantiate diagnosis.

Anterior horn syndrome: A rare manifestation of primary Sjögren's syndrome.

The authors report an exceptional case of an anterior horn syndrome associated with Sjögren's syndrome in a 58-year-old patient with a flaccid tetraparesis revealed by asymmetric atrophy and diffuse fasciculations associated with xerostomia and xerophthalmia. The electroneuromyography objectified a diffuse anterior horn syndrome. The brain MRI and spinal cord were normal. Laboratory tests revealed positive anti-SSA and anti-SSB antibody. The salivary glands biopsy objectified lymphocytic sialadenitis grade 3 of Chisholm. The Schirmer's test was abnormally low. Diagnosis of anterior horn syndrome as part of Sjögren's syndrome was retained. The methylprednisolone bolus allowed partial clinical improvement after 12 months of evolution. Therefore, in patients with isolated anterior horn involvement, a correct diagnosis of the underlying SS is often delayed or overlooked entirely; in these instances, standard clinicoserological assessment is recommendable.

Motor neurone disease and military service: evidence from the Scottish Veterans Health Study.

OBJECTIVES: In 2003, it was reported that motor neurone disease was linked to military service in the 1990-1991 Gulf War. A large study in the US confirmed an association with military service but found no association with specific conflicts or length of service. Non-veteran studies have suggested an association with physical activity, smoking and other risk factors. We used data from the Scottish Veterans Health Study to investigate the association between motor neurone disease and military service in UK veterans. METHODS: Retrospective cohort study of 57,000 veterans born 1945-1985, and 173,000 demographically matched civilians, using Cox proportional hazard models to compare the risk of motor neurone disease overall, and by sex, birth cohort, length of service and year of recruitment. We had no data on smoking prevalence. RESULTS: Veterans had an increased risk of motor neurone disease compared with non-veterans (adjusted HR 1.49, 95% CI 1.01 to 2.21, p=0.046). The increase was independent of birth cohort, length or period of service, or year of recruitment. Risk was associated with a history of trauma or road traffic accident in veterans and non-veterans. CONCLUSIONS: We confirmed an increased risk of motor neurone disease in military veterans, although the absolute risk is extremely low. We found no evidence that the increased risk was associated with any specific conflict. We could not rule out that smoking (and perhaps other lifestyle factors) may be responsible for our findings. Trauma may play a role in the increased risk but further studies are needed.

Paraneoplastic subacute lower motor neuron syndrome associated with solid cancer.

We retrospectively analyzed three patients with pure motor neuronopathy followed for more than four years in our center. The patients presented a rapidly progressive lower motor neuron syndrome (LMNS) over the course of a few weeks leading to a severe functional impairment. The neurological symptoms preceded the diagnosis of a breast adenocarcinoma and a thymoma in the first two patients, one of them with anti-CV2/CRMP5 antibodies. Cancer was not detected in the third patient who had circulating anti-Hu antibodies. A final diagnosis of paraneoplastic syndrome was made after investigations for alternative causes of lower motor neuron syndrome. Early diagnosis, combined treatment of the underlying cancer, and immunomodulatory treatment led to neurological improvement of the disease in two out of the three cases in which the cancer was diagnosed. Cases of subacute LMNS with rapid progression may occur as an expression of a paraneoplastic neurological syndrome. Identification of these syndromes is important, as the treatment of underlying malignancy along with immunomodulatory treatment may result in a favorable long-term outcome of these potentially fatal diseases.

[A case of motor dominant neuropathy and focal segmental glomerulosclerosis associated with Sjögren's syndrome].

A 49-year-old woman was admitted to our hospital with gradually progressive weakness of the limbs for about 20 days. She presented with weakness of the limbs, predominantly in the proximal portion, and slight dysesthesia of the limbs, predominantly in the distal portion. Repeated nerve conduction examination revealed axonopathy dominantly in the motor neurons. Therefore, we suspected her as having Guillain-Barré syndrome, and initiated intravenous administration of high-dose immunoglobulin. However, her symptoms progressed gradually and finally she found it difficult to walk. Her urine analysis simultaneously demonstrated albuminuria, and a kidney biopsy indicated focal segmental glomerulosclerosis. At that point, laboratory examination showed high levels of anti SS-A antibody and salivary gland biopsy revealed infiltration of a significant number of lymphocytes around the gland, which led to the diagnosis of Sjögren's syndrome. We considered the etiology of the neural and renal dysfunction as due to the inflammatory mechanism associated with Sjögren's syndrome. Therefore, we administered a second course of immunoglobulin therapy and steroid therapy, which included both pulse and oral administration. Her neurologic symptoms and albuminuria improved rapidly after steroid therapy. The present case indicates that both motor dominant neuropathy and focal segmental glomerulosclerosis can occur in patients with Sjögren's syndrome.

[Radiation-induced lumbosacral plexopathy with severe burning pain after 17 years of radiation therapy for cervical cancer: a case report].

A 73-year-old woman was admitted with severe burning pain, hyperesthesia, and weakness in the right lower extremity. The patient had undergone radio- and chemotherapy after surgery for cervical cancer 17 years earlier. We diagnosed radiation-induced lumbosacral plexopathy because of conduction block in the deep peroneal nerve and myokymic discharge in the tibialis anterior muscle. Pelvic computed tomography and magnetic resonance imaging ruled out recurrent tumor and nerve-compressing lesions. Although radiation-induced lumbosacral plexopathy is usually characterized by lower motor neuron syndrome, we report a rare case presenting with severe pain and hyperesthesia.

Two cases of multinodular and vacuolating neuronal tumour.

An unusual multinodular and vacuolating neuronal tumour (MVNT) has been described in the cerebral hemispheres of ten patients with adult-onset seizures. We report the findings in two cases with similar features, a surgical resection and the other an autopsy specimen.Case 1, a 34-year-old female, underwent surgical resection for a multinodular non-enhancing frontal white matter lesion causing intractable epilepsy. Case 2, presented with motor neurone disease (MND) at the age of 71 and MRI scanning revealed extensive multinodular non-enhancing white matter lesions in the temporal lobe. There was no history of epilepsy and post mortem histology confirmed MND.Macroscopically multiple small grey well-formed, discrete and coalescent nodules were seen in the deep cortex and subcortical white matter. On histology, mature-looking neurons with large cytoplasmic vacuoles were distributed in a fibrillary background, where vacuoles were also noted. In the resected tumour scattered oligodendroglia-like cells were present. No ganglion cells were seen. The vacuolated cells exhibited immunopositivity for synaptophysin, HuC/HuD and p62 but were negative for NeuN, neurofilament, GFAP, IDH1, nestin and CD34. Electron microscopy showed non-membrane bound cytoplasmic vacuoles in the neurons and in some neuronal processes. The seizures recurred in Case 1.Some clinicopathological features of this lesion suggest a possible relationship with dysembryoplastic neuroepithelial tumour (DNT) although the morphological features are not typical of DNT. Case 2 demonstrates that MVNT may remain asymptomatic.

Activation of microglial neuregulin1 signaling in the corticospinal tracts of ALS patients with upper motor neuron signs.

We recently found neuregulin1 (NRG1) receptors are activated on microglia in the ventral horn of both ALS patients and SOD1 mice, suggesting a common pathological mechanism. However, it is not clear whether this signaling system also plays a role in patients with upper motor neuron (UMN) features, where patients show significant pathological changes in the corticospinal tracts (CSTs). Since the connection between upper and lower motor neuron (LMN) systems in ALS patients is not readily seen in the SOD1 mouse, we examined the lateral and ventral CSTs for NRG1 receptor activation and NRG1 expression in ALS patients with UMN symptoms compared to control patients with no evidence of neurodegenerative disease. We found that ALS patients with UMN symptoms showed increased microglial activation that colocalized with NRG1 receptor activation in the lateral and ventral CSTs. These same regions also showed increased NRG1 protein expression locally but no change in NRG1 mRNA. In conclusion, these data suggest that increased NRG1 protein accumulation could contribute to UMN disease through microglial activation in the CSTs.

A retrospective audit of 200 cases of CNS tumours and their surgical management in a tertiary care centre.

AIMS: To study the nature of the tumours managed in the Irish population. METHODS: This audit research was completed via a retrospective medical review on 200 patients with CNS tumours managed in a tertiary care centre between 2008 and 2009. RESULTS: The mean age was 53 years. The male:female ratio was 2:1. The majority were glioblastomas and astrocytomas. Grade IV tumours were predominant (65.5 %). Headaches (37 %), motor weakness (32 %) and seizures (25.5 %) were the highest presentations. The commonest sites affected were the left parietal and left temporal lobes. There were 17.5 % operative morbidities with motor weakness (22.9 %), seizure (14.3 %) and thrombo-embolism (14.3 %) dominating and significant association to surgical radicality (p = 0.041). 3.5 % operative mortalities were reported. 52.5 and 62.5 % of patients received adjuvant chemotherapy and radiotherapy, respectively. CONCLUSIONS: Patients with CNS tumours typically had multiple presentations. More extensive surgical resection was associated with higher postoperative morbidities (p = 0.041). The 30-day postoperative morbidity (17.5 %) and mortality (3.5 %) were concordant with the currently available literature.

Postradiation lower motor neuron syndrome: case series and literature review.

A variety of neurological syndromes has been described after irradiation of the distal spinal cord and cauda equina, mainly as treatment for testicular cancer and lymphoma. One of these syndromes is a rare lower motor neuron syndrome, manifested by flaccid paraparesis. Medical files of patients with postradiation lower motor neuron syndrome treated in our neuromuscular clinic from 2005 to 2012 were reviewed. The diagnosis was based on past irradiation of the distal spinal cord and cauda equina, slowly progressive lower limb weakness, characteristic electrophysiological studies, and no alternative diagnosis. In addition, a systematic review of the literature on similar cases was performed using PUBMED. We identified five patients with postradiation lower motor neuron syndrome in our clinic charts. Three of them were irradiated due to seminoma, and the other two due to lymphoma. 45 additional similar cases were found in a literature search, mainly male (89 %), with testicular cancer (67 %), irradiated at mean age of 33 years, with an average irradiation dose of 5,225 cGy (range 3,000-14,600), and a latency period between irradiation and symptoms onset ranging from 3 months to 27 years (average 9 years). Magnetic resonance imaging was done only in few, showing gadolinium enhancement of the cauda equina in close to half of them (7/16). Our patients and those previously described in the literature form a distinct clinical and electrophysiological syndrome that might be more frequent then previously expected, and should be not overlooked.

Occupational exposure to extremely low-frequency magnetic fields and neurodegenerative disease: a meta-analysis.

OBJECTIVE: Previous studies reported associations of occupational electric and magnetic fields (MF) with neurodegenerative diseases (NDDs). Results differ between studies using proxy exposure based on occupational titles and estimated MF levels. We conducted a meta-analysis of occupational MF NDD, primarily Alzheimer disease (AD), and motor neuron diseases (MNDs) studies. METHODS: We identified 42 peer-reviewed publications and focused our analysis on study characteristics, exposure metrics, and publication bias. RESULTS: We found weak associations for occupational MF exposure proxies with AD and MND. Motor neuron disease risk was associated with occupational titles, whereas AD risk was associated with estimated MF levels. Results varied in study design, with dissimilar variation across diseases. CONCLUSIONS: Our results do not support MF as the explanation for observed associations between occupational titles and MND. Disease misclassification, particularly for AD, and imprecise exposure assessment affected most studies.

Lower motor neuron syndrome due to cauda equina hypertrophy with onion bulbs.

INTRODUCTION: Hypertrophy of the nerve roots of the cauda equina may occur with both acquired and inherited neuropathies. Although selective nerve root involvement of the sensory roots has been described and termed chronic inflammatory sensory polyradiculoneuropathy (CISP), selective involvement of the proximal motor roots has not been described. METHODS: Clinical, electrophysiological, MRI, and pathological findings are reported. RESULTS: Here, we report a patient with cauda equina hypertrophy presenting with a pure lower motor neuron syndrome without clinical or electrophysiological evidence of sensory fiber involvement. Bowel and bladder functions were spared. Nerve root biopsy demonstrated abundant onion bulb formations. The patient experienced improvement in motor function with immunomodulatory treatment. CONCLUSIONS: We suggest the term chronic immune demyelinating motor polyradiculopathy (CIMP) to describe this particular form of CIDP, thereby expanding the clinical spectrum of CIDP.