Fast Progression in Amyotrophic Lateral Sclerosis Is Associated With Greater TDP-43 Burden in Spinal Cord

Upper and lower motor neuron pathologies are critical to the autopsy diagnosis of amyotrophic lateral sclerosis (ALS). Further investigation is needed to determine how the relative burden of these pathologies affects the disease course. We performed a blinded, retrospective study of 38 ALS patients, examining the association between pathologic measures in motor cortex, hypoglossal nucleus, and lumbar cord with clinical data, including progression rate and disease duration, site of symptom onset, and upper and lower motor neuron signs. The most critical finding in our study was that TAR DNA-binding protein 43 kDa (TDP-43) pathologic burden in lumbar cord and hypoglossal nucleus was significantly associated with a faster progression rate with reduced survival (p < 0.02). There was no correlation between TDP-43 burden and the severity of cell loss, and no significant clinical associations were identified for motor cortex TDP-43 burden or severity of cell loss in motor cortex. C9orf72 expansion was associated with shorter disease duration (p < 0.001) but was not significantly associated with pathologic measures in these regions. The association between lower motor neuron TDP-43 burden and fast progression with reduced survival in ALS provides further support for the study of TDP-43 as a disease biomarker.

Tracking white and grey matter degeneration along the spinal cord axis in degenerative cervical myelopathy

ObjectiveTo determine tissue-specific neurodegeneration across the spinal cord in patients with mild-moderate degenerative cervical myelopathy (DCM).MethodsTwenty-four mild-moderate DCM and 24 healthy subjects were recruited. In patients, a T2-weighted scan was acquired at the compression site, while in all participants a T2*-weighted and diffusion-weighted scan was acquired at the cervical level (C2-C3) and in the lumbar enlargement (i.e. rostral and caudal to the site of compression). We quantified intramedullary signal changes, maximal canal and cord compression, white (WM) and grey matter (GM) atrophy, and microstructural indices from diffusion-weighted scans. All patients underwent clinical (modified Japanese Orthopaedic Association (mJOA)) and electrophysiological assessments. Regression analysis assessed associations between MRI readouts and electrophysiological and clinical outcomes.ResultsTwenty patients were classified with mild and four with moderate DCM using the mJOA scale. The most frequent site of compression was at C5-C6 level with maximum cord compression of 4.68±0.83 mm. Ten patients showed imaging evidence of cervical myelopathy. In the cervical cord, WM and GM atrophy and WM microstructural changes were evident, while in the lumbar cord only WM showed atrophy and microstructural changes. Remote cervical cord WM microstructural changes were pronounced in patients with radiological myelopathy and associated with impaired electrophysiology. Lumbar cord WM atrophy was associated with lower limb sensory impairments.ConclusionTissue-specific neurodegeneration revealed by quantitative MRI, already apparent across the spinal cord in mild-moderate DCM prior to the onset of severe clinical impairments. WM microstructural changes are particularly sensitive to remote pathologically and clinically eloquent changes in DCM.

Transcutaneous spinal cord stimulation of the cervical cord modulates lumbar networks

It has been established that coordinated arm and leg (A&L) cycling facilitates corticospinal drive and modulation of cervico-lumbar connectivity and ultimately improves overground walking in people with incomplete spinal cord injury or stroke. This study examined the effect of noninvasive transcutaneous spinal cord stimulation (tSCS) on the modulation of cervico-lumbar connectivity. Thirteen neurologically intact adults participated in the study. The excitability of the Hoffmann (H) reflex elicited in the soleus muscle was examined under multiple conditions involving either the arms held in a static position or rhythmic arm cycling while tSCS was applied to either the cervical or lumbar cord. As expected, soleus H-reflex amplitude was significantly suppressed by 19.2% during arm cycling (without tSCS) relative to arms static (without tSCS). Interestingly, tSCS of the cervical cord with arms static significantly suppressed the soleus H-reflex (−22.9%), whereas tSCS over the lumbar cord did not suppress the soleus H-reflex (−3.8%). The combination of arm cycling with cervical or lumbar tSCS did not yield additional suppression of the soleus H-reflex beyond that obtained with arm cycling alone or cervical tSCS alone. The results demonstrate that activation of the cervical spinal cord through both rhythmic arm cycling and tonic tSCS significantly modulates the activity of lumbar networks. This highlights the potential for engaging cervical spinal cord networks through tSCS during rehabilitation interventions to enhance cervico-lumbar connectivity. This connectivity is influential in facilitating improvements in walking function after neurological impairment. NEW & NOTEWORTHY This is the first study to investigate the modulatory effects of transcutaneous spinal cord stimulation (tSCS) on cervico-lumbar connectivity. We report that both rhythmic activation of the cervical spinal cord through arm cycling and tonic activation of the cervical cord through tSCS significantly modulate the activity of lumbar networks. This suggests that engaging cervical spinal cord networks through tSCS during locomotor retraining interventions may not only enhance cervico-lumbar connectivity but also further improve walking capacity.

Acute Transverse Myelitis Related to Mycoplasma pneumonia

We present a case of transverse myelitis caused by Mycoplasma pneumonia. Clinical findings were muscle weakness and decreased deep tendon reflexes of the lower extremities, total sensory loss below T8 level, including loss of superficial cutaneous abdominal reflexes bilaterally, and urinary and stool incontinence. Magnetic resonance imaging revealed segmental edema extending from the cervical to the lumbar cord. Serological criteria were used for the diagnosis of acute infection caused by M. pneumonia. The patient recovered completely after a 15-day treatment of intravenous clarithromycin accompanied by pulsed methylprednisolone. This report emphasizes that myelitis is one of the most severe central nervous system complications related to M. pneumonia infections, and early treatment helps to avoid complications.

Motoneurons regulate the central pattern generator during drug-induced locomotor-like activity in the neonatal mouse

Motoneurons are traditionally viewed as the output of the spinal cord that do not influence locomotor rhythmogenesis. We assessed the role of motoneuron firing during ongoing locomotor-like activity in neonatal mice expressing archaerhopsin-3 (Arch), halorhodopsin (eNpHR), or channelrhodopsin-2 (ChR2) in Choline acetyltransferase neurons (ChAT+) or Arch in LIM-homeodomain transcription factor Isl1+ neurons. Illumination of the lumbar cord in mice expressing eNpHR or Arch in ChAT+ or Isl1+ neurons, depressed motoneuron discharge, transiently decreased the frequency, and perturbed the phasing of the locomotor-like rhythm. When the light was turned off motoneuron firing and locomotor frequency both transiently increased. These effects were not due to cholinergic neurotransmission, persisted during partial blockade of gap junctions and were mediated, in part, by AMPAergic transmission. In spinal cords expressing ChR2, illumination increased motoneuron discharge and transiently accelerated the rhythm. We conclude that motoneurons provide feedback to the central pattern generator (CPG) during drug-induced locomotor-like activity.

Hemophagocytic lymphohistiocytosis, an unclear nosologic entity: case report of an adult man with rising of amylase and lipase and spinal cord infiltration

Here we present the case of a 57-years old patient affected by hemophagocytic lymphohistiocytosis (HLH), a rare disease characterized by an uncontrolled immune activation, resulting in clinical and biochemical manifestations of extreme inflammation. In a previous hospitalization, the patient showed fever, hepato-splenomegaly, pancytopenia, hyperferrtitinemia, lymphadenopathy and cholestasis. No diagnosis was done, however, he totally recovered after splenectomy. Eight months later, he relapsed, showing also hypofibrinogenemia, hypertriglyceridemia, hemophagocytic signs in bone marrow, cholestatic jaundice, high LDH and high PT-INR. Interestingly, he presented increased levels of amylase and lipase in absence of radiologic signs of pancreatitis. He was treated with Dexamethasone and Cyclosporine according to HLH-2004 guidelines. The clinical and biochemical manifestations disappeared in a few weeks, but he was newly hospitalized for lower limbs hypotonia caused by a hemophagocytic lesion of the cauda equina and lumbar cord. The death occurred in a few days, despite the immunosuppressive treatment.