Motor neuron disease in patients with HIV infection: Report of two cases and brief review of the literature.

HIV-associated motor neuron disease (MND), or amyotrophic lateral sclerosis (ALS)-like syndrome associated with HIV infection, is a rare manifestation of HIV infection. HIV-associated MND has only been identified in few cases to date. We analysed two Brazilian patients with HIV infection who developed MND. The diagnosis of HIV infection was concomitant with diagnosis of MND in one patient and it occurred eight years before the MND symptoms in another patient. The manifestation of MND in our patients with HIV infection was similar to classic ALS. The antiretroviral therapy improves their HIV infection. However, slow progression of MND occurred in the two patients despite their antiretroviral therapy or HIV viral load (undetectable). We revised the international literature (PubMed database) of the patients reported with MND and HIV infection.

HIV-associated motor neuron disease: HERV-K activation and response to antiretroviral therapy.

OBJECTIVE: To determine whether there is activation of human endogenous retrovirus K (HERV-K) in amyotrophic lateral sclerosis in HIV infection and whether it might respond to treatment with antiretroviral drugs. METHODS: In this case series, we present 5 patients with HIV infection who subsequently developed motor neuron disease involving both upper and lower motor neurons. We monitored HERV-K levels in plasma of 4 of these patients. RESULTS: Three patients who received antiretroviral therapy had reversal of symptoms within 6 months of onset of neurologic symptoms and the other 2 had slow neurologic progression over several years. Three patients in whom the levels were measured at onset of neurologic symptoms showed elevated HERV-K levels that responded to optimization of antiretroviral therapy for CNS penetration. CONCLUSIONS: Thus, motor neuron disease in individuals with HIV infection may a treatable entity, but early treatment with CNS-penetrating antiretroviral therapy may be necessary. Monitoring of HERV-K levels may help guide treatment.

Ecotropic Murine Leukemia Virus Infection of Glial Progenitors Interferes with Oligodendrocyte Differentiation: Implications for Neurovirulence.

UNLABELLED: Certain murine leukemia viruses (MLVs) are capable of inducing fatal progressive spongiform motor neuron disease in mice that is largely mediated by viral Env glycoprotein expression within central nervous system (CNS) glia. While the etiologic mechanisms and the glial subtypes involved remain unresolved, infection of NG2 glia was recently observed to correlate spatially and temporally with altered neuronal physiology and spongiogenesis. Since one role of NG2 cells is to serve as oligodendrocyte (OL) progenitor cells (OPCs), we examined here whether their infection by neurovirulent (FrCasE) or nonneurovirulent (Fr57E) ecotropic MLVs influenced their viability and/or differentiation. Here, we demonstrate that OPCs, but not OLs, are major CNS targets of both FrCasE and Fr57E. We also show that MLV infection of neural progenitor cells (NPCs) in culture did not affect survival, proliferation, or OPC progenitor marker expression but suppressed certain glial differentiation markers. Assessment of glial differentiation in vivo using transplanted transgenic NPCs showed that, while MLVs did not affect cellular engraftment or survival, they did inhibit OL differentiation, irrespective of MLV neurovirulence. In addition, in chimeric brains, where FrCasE-infected NPC transplants caused neurodegeneration, the transplanted NPCs proliferated. These results suggest that MLV infection is not directly cytotoxic to OPCs but rather acts to interfere with OL differentiation. Since both FrCasE and Fr57E viruses restrict OL differentiation but only FrCasE induces overt neurodegeneration, restriction of OL maturation alone cannot account for neuropathogenesis. Instead neurodegeneration may involve a two-hit scenario where interference with OPC differentiation combined with glial Env-induced neuronal hyperexcitability precipitates disease. IMPORTANCE: A variety of human and animal retroviruses are capable of causing central nervous system (CNS) neurodegeneration manifested as motor and cognitive deficits. These retroviruses infect a variety of CNS cell types; however, the specific role each cell type plays in neuropathogenesis remains to be established. The NG2 glia, whose CNS functions are only now emerging, are a newly appreciated viral target in murine leukemia virus (MLV)-induced neurodegeneration. Since one role of NG2 glia is that of oligodendrocyte progenitor cells (OPCs), we investigated here whether their infection by the neurovirulent MLV FrCasE contributed to neurodegeneration by affecting OPC viability and/or development. Our results show that both neurovirulent and nonneurovirulent MLVs interfere with oligodendrocyte differentiation. Thus, NG2 glial infection could contribute to neurodegeneration by preventing myelin formation and/or repair and by suspending OPCs in a state of persistent susceptibility to excitotoxic insult mediated by neurovirulent virus effects on other glial subtypes.

Human endogenous retrovirus-K contributes to motor neuron disease.

The role of human endogenous retroviruses (HERVs) in disease pathogenesis is unclear. We show that HERV-K is activated in a subpopulation of patients with sporadic amyotrophic lateral sclerosis (ALS) and that its envelope (env) protein may contribute to neurodegeneration. The virus was expressed in cortical and spinal neurons of ALS patients, but not in neurons from control healthy individuals. Expression of HERV-K or its env protein in human neurons caused retraction and beading of neurites. Transgenic animals expressing the env gene developed progressive motor dysfunction accompanied by selective loss of volume of the motor cortex, decreased synaptic activity in pyramidal neurons, dendritic spine abnormalities, nucleolar dysfunction, and DNA damage. Injury to anterior horn cells in the spinal cord was manifested by muscle atrophy and pathological changes consistent with nerve fiber denervation and reinnervation. Expression of HERV-K was regulated by TAR (trans-activation responsive) DNA binding protein 43, which binds to the long terminal repeat region of the virus. Thus, HERV-K expression within neurons of patients with ALS may contribute to neurodegeneration and disease pathogenesis.

Muscular weakness in individuals with HIV associated with a disorganization of the cortico-spinal tract: a multi-modal MRI investigation.

Motor impairment is highly prevalent in HIV-infected patients. Here, we assess associations between peripheral muscular deficits as evaluated by the 5 sit-to-stand test (5STS) and structural integrity of the motor system at a central level. Eighty-six HIV-infected patients receiving combination antiretroviral therapy and with no major cerebral events, underwent an MRI scan and the 5STS. Out of 86 participants, forty presented a score greater than two standard deviations above mean normative scores calculated for the 5STS and were therefore considered as motor-impaired. MRI-structural cerebral parameters were compared to the unimpaired participants. Fractional Anisotropy (FA), Axial Diffusivity (AD) and Radial Diffusivity (RD), reflecting microstructural integrity, were extracted from Diffusion-Tensor MRI. Global and regional cerebral volumes or thicknesses were extracted from 3D-T1 morphological MRI. Whereas the two groups did not differ for any HIV variables, voxel-wise analysis revealed that motor-impaired participants present low FA values in various cortico-motor tracts and low AD in left cortico-spinal tract. However, they did not present reduced volumes or thicknesses of the precentral cortices compared to unimpaired participants. The absence of alterations in cortical regions holding motor-neurons might argue against neurodegenerative process as an explanation of White Matter (WM) disorganization.

Misfolding of CasBrE SU is reversed by interactions with 4070A Env: implications for gammaretroviral neuropathogenesis.

BACKGROUND: CasBrE is a neurovirulent murine leukemia virus (MLV) capable of inducing paralytic disease with associated spongiform neurodegeneration. The neurovirulence of this virus has been genetically mapped to the surface expressed subunit (SU) of the env gene. However, CasBrE SU synthesized in the absence of the transmembrane subunit (TM) does not retain ecotropic receptor binding activity, indicating that folding of the receptor binding domain (RBD) requires this domain. Using a neural stem cell (NSC) based viral trans complementation approach to examine whether misfolded CasBrE SU retained neurovirulence, we observed CasBrE SU interaction with the "non-neurovirulent" amphotropic helper virus, 4070A which restored functional activity of CasBrE SU. RESULTS: Herein, we show that infection of NSCs expressing CasBrE SU with 4070A (CasES+4070A-NSCs) resulted in the redistribution of CasBrE SU from a strictly secreted product to include retention on the plasma membrane. Cell surface cross-linking analysis suggested that CasBrE SU membrane localization was due to interactions with 4070A Env. Viral particles produced from CasES+4070A-NSCS contained both CasBrE and 4070A gp70 Env proteins. These particles displayed ecotropic receptor-mediated infection, but were still 100-fold less efficient than CasE+4070A-NSC virus. Infectious center analysis showed CasBrE SU ecotropic transduction efficiencies approaching those of NSCs expressing full length CasBrE Env (CasE; SU+TM). In addition, CasBrE SU-4070A Env interactions resulted in robust ecotropic superinfection interference indicating near native intracellular SU interaction with its receptor, mCAT-1. CONCLUSIONS: In this report we provided evidence that 4070A Env and CasBrE SU physically interact within NSCs leading to CasBrE SU retention on the plasma membrane, incorporation into viral particles, restoration of mCAT-1 binding, and capacity for initiation of TM-mediated fusion events. Thus, heterotropic Env-SU interactions facilitates CasBrE SU folding events that restore Env activity. These findings are consistent with the idea that one protein conformation acts as a folding scaffold or nucleus for a second protein of similar primary structure, a process reminiscent of prion formation. The implication is that template-based protein folding may represent an inherent feature of neuropathogenic proteins that extends to retroviral Envs.

Acute motor axonal neuropathy associated with pandemic H1N1 influenza A infection.

BACKGROUND: Guillain-Barre syndrome (GBS) is a well known entity that has many infectious agents reported as antecedent events. The spectrum of GBS includes acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor sensory axonal neuropathy (AMSAN), and some other variants like Miller-Fisher syndrome (MFS). METHODS: Patient with AMAN variant of GBS after severe bilateral pneumonia and ARDS due to the novel pandemic H1N1 influenza A virus is presented. RESULTS: 28-year-old white female was admitted to our Intensive Care Unit during the influenza pandemic because of severe ARDS due to bilateral pneumonia. The course of the disease was complicated with the new onset tetraplegia due to the AMAN variant of GBS. Treatment with plasma exchange was conducted and the patient had satisfactory recovery. CONCLUSION: We report a case of AMAN variant of GBS associated with proven H1N1 influenza A infection. This virus has not been reported previously as the agent of antecedent infection that induced this disorder. Risk factors for other causes of ICU neuromuscular weakness are usually present in the ICU patients and should not be the reason for reluctance in active quest for GBS. Once the diagnosis of GBS is established or suspected the treatment with plasma exchange or intravenous immune globulin is indicated.

Pure motor Herpes Zoster induced brachial plexopathy.

Brachial plexus neuritis in the presence of herpes zoster infection is uncommon. Motor involvement is probably due to the spreading of inflammation from the dorsal root ganglia to the ventral roots and may be more extensive than the affected dermatomes. We present a case of herpes zoster brachial plexopathy with pure motor involvement both clinically and electrophysiologically.

Persistent West Nile virus associated with a neurological sequela in hamsters identified by motor unit number estimation.

To investigate the hypothesis that neurological sequelae are associated with persistent West Nile virus (WNV) and neuropathology, we developed an electrophysiological motor unit number estimation (MUNE) assay to measure the health of motor neurons temporally in hamsters. The MUNE assay was successful in identifying chronic neuropathology in the spinal cords of infected hamsters. MUNE was suppressed at days 9 to 92 in hamsters injected subcutaneously with WNV, thereby establishing that a long-term neurological sequela does occur in the hamster model. MUNE suppression at day 10 correlated with the loss of neuronal function as indicated by reduced choline acetyltransferase staining (R(2) = 0.91). Between days 10 and 26, some alpha-motor neurons had died, but further neuronal death was not detected beyond day 26. MUNE correlated with disease phenotype, because the lowest MUNE values were detected in paralyzed limbs. Persistent WNV RNA and foci of WNV envelope-positive cells were identified in the central nervous systems of all hamsters tested from 28 to 86 days. WNV-positive staining colocalized with the neuropathology, which suggested that persistent WNV or its products contributed to neuropathogenesis. These results established that persistent WNV product or its proteins cause dysfunction, that WNV is associated with chronic neuropathological lesions, and that this neurological sequela is effectively detected by MUNE. Inasmuch as WNV-infected humans can also experience a poliomyelitis-like disease where motor neurons are damaged, MUNE may also be a sensitive clinical or therapeutic marker for those patients.

Experimental reovirus-induced acute flaccid paralysis and spinal motor neuron cell death.

Acute flaccid paralysis (AFP) describes the loss of motor function in 1 or more limbs commonly associated with viral infection and destruction of motor neurons in the anterior horns of the spinal cord. Therapy is limited, and the development of effective treatments is hampered by a lack of experimental models. Reovirus infection of neonatal mice provides a model for the study of CNS viral infection pathogenesis. Injection of the Reovirus serot Type 3 strains Abney (T3A) or Dearing (T3D) into the hindlimb of 1-day-old mice resulted in the development of AFP in more than 90% of infected mice. Acute flaccid paralysis began in the ipsilateral hindlimb at 8 to 10 days postinfection and progressed to paraplegia 24 hours later. Paralysis correlated with injury, neuron loss, and spread of viral antigen first to the ipsilateral and then to the contralateral anterior horns. As demonstrated by the activation of caspase 3 and its colocalization with viral antigen in the anterior horn and concomitant cleavage of poly-(adenosine diphosphate-ribose) polymerase, AFP was associated with apoptosis. Calpain activity and inducible nitric oxide synthase expression were both elevated in the spinal cords of paralyzed animals. This study represents the first detailed characterization of a novel and highly efficient experimental model of virus-induced AFP that will facilitate evaluation of therapeutic strategies targeting virus-induced paralysis.

Are enteroviral receptors different in sporadic motor neuron disease?

Enteroviruses have been suspected to play a part in the pathogenesis of sporadic motor neuron disease (SMND). Intercellular adhesion molecule type-1 (ICAM1) and coxsackie and adenovirus receptor (CAR) act as receptors for a number of enteroviruses. We therefore examined the viral binding domains of ICAM1 and CAR to see if any changes could be found that might predispose to enteroviral infections. Single nucleotide polymorphisms in the ICAM1 viral binding domain, the adjacent intron and a region implicated in other neurological disorders, as well as the CAR viral binding regions in exons 2-5, were compared in 139 SMND patients and 139 matched controls. The distribution of the polymorphisms was similar in both groups. Therefore, based on linkage disequilibrium and genotype it is unlikely that either ICAM1 or CAR is implicated in SMND.

Flaviviruses in motor neuron disease.

Sporadic motor neuron disease (MND) causes a progressive loss of motor neurons. West Nile virus can attack motor neurons, so we examined whether flavivirus infection could be detected in MND cases. Spinal cord sections from 22 MND cases were stained immunohistochemically with a flavivirus-specific antibody. No staining for flavivirus was seen in any case. Sporadic MND does not appear to arise from a recent infection with a flavivirus.

HIV-1 clade-C-associated "ALS"-like disorder: first report from India.

A patient of ALS-like disorder in an HIV-1 clade-C-infected heterosexual male is being reported. A 37-year-old gentleman presented with subacute, progressive asymmetrical onset of weakness and wasting of upper limbs associated with brisk muscle stretch reflexes and without any sensory or sphincter involvement. While nerve conduction tests were normal, the EMG of proximal and distal limb muscles on both sides revealed evidence of denervation and reinnervation. Routine blood and urine tests and investigations for underlying causes of motor neuron disease were noncontributory. He was HIV-1, subtype clade C seropositive. A diagnosis of HIV-related anterior horn cell disease was considered and zidovudine, lamivudine and nevirapine were started. After 1 month, there was a subjective improvement of 10% and objective improvement in strength of muscles of proximal upper limb on both sides by one grade power on MRC scale. Reports of amyotrophic lateral sclerosis (ALS)-like illness in HIV are sparse. The reversibility of "ALS"-like features in this subgroup of patients might offer an insight into the pathogenesis of amyotrophic lateral sclerosis. This is a first report of ALS-like illness caused by subtype C of HIV-1 strain.

[Virus-like inclusions in the myocytes of the skeletal muscle in lateral amyotrophic sclerosis]. / Virusopodobnye vkliucheniia v miotsitah skeletnoy myshtsy pri bokovom amiotroficheskom sklerose.

Microscopic examination of musculus gastrocnemius biopsies was made in four cases of sporadic lateral amyotrophic sclerosis (LAS). The validity of the clinical diagnosis was confirmed by detected neurotrophic atrophy of the muscular fibers typical for LAS. Electron microscopic study revealed virus-like inclusions 200-450 nm in size in sarcoplasm of myocytes of all the patients. The inclusions consist of lined cells of hexagonal shape at the distance of 37-41 nm from each other. The inclusions resemble enteroviruses but are not identical to them both by size and structure of their elements. There were also specific ultrastructural changes of myocytes corresponding to viral infection. The above virus-like inclusions should be considered as specific structures formed as a result of metabolic shifts caused by productive action on the cell of infective or unknown factor.

Evidence for neuronal localisation of enteroviral sequences in motor neurone disease/amyotrophic lateral sclerosis by in situ hybridization.

Sequences resembling those of human enterovirus type B sequences have been associated with motor neurone disease/amyotrophic lateral sclerosis. In a previous study we detected enteroviral sequences in spinal cord/brain stem from cases of motor neurone disease/amyotrophic lateral sclerosis, but not controls. Adjacent tissue sections to two of those strongly positive for these sequences by reverse-transcriptase polymerase chain reaction were analyzed by in situ hybridization with digoxigenin-labelled virus-specific antisense riboprobes. In one case, a female aged 83 showing 12 month rapid progressive disease, signal was specifically localized to cells identifiable as motor neurones of the anterior horn. In another case, a male aged 63 with a 60-month history of progressive muscle weakness, dysarthia, dyspnoea and increased tendon reflexes, signal was located to neurones in the gracile/cuneate nuclei of the brain stem tissue block that had been analyzed. This case showed loss of neurones in the anterior horn of the spinal cord by histopathologic examination which would account for clinical signs of motor neurone disease/amyotrophic lateral sclerosis. Dysfunction of the gracile/cuneate nuclei might have been masked by the paralytic disease. These structures are adjacent to the hypoglossal nuclei, and suggest either localised dissemination from hypoglossal nuclei or a possible route of dissemination of infection through the brainstem to the hypoglossal nuclei. These findings provide further evidence for the possible involvement of enteroviruses in motor neurone disease/amyotrophic lateral sclerosis.