Haemorrhagic conversion of infectious myelitis in an immunocompromised patient.

A 28-year-old man recently diagnosed with HIV (CD4 19 cells/mm3, viral load 3.6 million copies/mL, not on highly active antiretroviral therapy on initial diagnosis at outside hospital), disseminated histoplasmosis, shingles and syphilis presented with paraplegia developing over 3 days. Spine MRI demonstrated a longitudinally extensive cord lesion extending from C3 to the tip of the conus. Brain MRI was consistent with meningoencephalitis. Cerebrospinal fluid findings were notable for positive varicella zoster virus (VZV) and cytomegalovirus (CMV) PCRs as well as a Venereal Disease Research Laboratory titre of 1:2. Patient was started on treatment for VZV and CMV meningoencephalitis, neurosyphilis and high-dose steroids for infectious myelitis. Repeat spine MRI demonstrated subacute intramedullary haemorrhage of the cervical cord. He was ultimately discharged to a skilled nursing facility for long-term intravenous antiviral therapy and rehabilitation. After 59 days in the hospital, his neurological exam remained grossly unchanged, with flaccid paraplegia and lack of sensation to fine touch in his lower extremities.

GLT1 overexpression in SOD1(G93A) mouse cervical spinal cord does not preserve diaphragm function or extend disease.

Amyotrophic lateral sclerosis (ALS) is characterized by relatively rapid degeneration of both upper and lower motor neurons, with death normally occurring 2-5years following diagnosis primarily due to respiratory paralysis resulting from phrenic motor neuron (PhMN) loss and consequent diaphragm denervation. In ALS, cellular abnormalities are not limited to MNs. For example, decreased levels and aberrant functioning of the major central nervous system (CNS) glutamate transporter, GLT1, occur in spinal cord and motor cortex astrocytes of both humans with ALS and in SOD1(G93A) rodents, a widely studied ALS animal model. This results in dysregulation of extracellular glutamate homeostasis and consequent glutamate excitotoxicity, a primary mechanism responsible for MN loss in ALS animal models and in the human disease. Given these observations of GLT1 dysfunction in areas of MN loss, as well as the importance of testing therapeutic strategies for preserving PhMNs in ALS, we evaluated intraspinal delivery of an adeno-associated virus type 8 (AAV8)-Gfa2 vector to the cervical spinal cord ventral horn of SOD1(G93A) ALS mice for focally restoring intraspinal GLT1 expression. AAV8 was specifically injected into the ventral horn bilaterally throughout the cervical enlargement at 110days of age, a clinically-relevant time point coinciding with phenotypic/symptomatic disease onset. Intraspinal delivery of AAV8-Gfa2-GLT1 resulted in robust transduction primarily of GFAP(+) astrocytes that persisted until disease endstage, as well as a 2-3-fold increase in total intraspinal GLT1 protein expression in the ventral horn. Despite this robust level of astrocyte transduction and GLT1 elevation, GLT1 overexpression did not protect PhMNs, preserve histological PhMN innervation of the diaphragm NMJ, or prevent decline in diaphragmatic respiratory function as assessed by phrenic nerve-diaphragm compound muscle action potential (CMAP) recordings compared to control AAV8-Gfa2-eGFP injected mice. In addition, AAV-Gfa2-GLT1 did not delay forelimb disease onset, extend disease duration (i.e. time from either forelimb or hindlimb disease onsets to endstage) or prolong overall animal survival. These findings suggest that focal restoration of GLT1 expression in astrocytes of the cervical spinal cord using AAV delivery is not an effective therapy for ALS.