|Year : 2006 | Volume
| Issue : 2 | Page : 103-109
Spectrum of motor neuron diseases with HIV-1 infection
Ashok Verma1, Shri Kant Mishra2
1 Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA
2 Department of Neurology, University of Southern California Keck School of Medicine Los Angeles, California, USA
1150 NW 14 Street, Suite 701, Miami, FL 33136
Source of Support: None, Conflict of Interest: None
Background: The cause of sporadic motor neuron disease (MND) or amyotrophic lateral sclerosis (ALS) is unknown. During the last 20 years, at least 23 cases of MND have been reported in HIV-1 (HIV) seropositive individuals. Objective: To describe two patients with HIV infection and MND and to review the literature regarding HIV-associated MND. Setting: A multidisciplinary ALS center and Neuro-AIDS clinic at tertiary care university hospitals. Patients/Design: We prospectively studied two HIV-infected patients with motor neuron disease. A detailed review of the literature employing the PubMed search strategy revealed 23 additional cases of MND in HIV-infected persons. These were reviewed for comparison and contrast with the characteristics of sporadic classical MND. Results: The clinical features of MND in our two cases, mirrored that of the sporadic MND (upper and lower motor neuron disorder) and primary lateral sclerosis (PLS, isolated upper motor neuron disorder). The review of 23 previously reported patients with MND and HIV infection revealed that they could be categorized into clinically definite MND (6 cases) or clinically probable or possible MND (17 cases). MND commenced at different stages of the HIV; in 9 patients HIV infection was discovered contemporaneously with the diagnosis of MND. As in our one patient, 14 of 18 patients with HIV-associated MND syndrome receiving highly active antiretroviral therapy (HAART), demonstrated at least partial recovery of their motor deficit. Conclusions: A clinical picture similar to MND or PLS may occur in association with HIV infection. An aggressive HAART regimen to reduce viral load should be pursued in all such cases.
Keywords: Dysarthria, highly active antiretroviral therapy, human immunodeficiency virus type 1, motor neuron disease, primary lateral sclerosis
|How to cite this article:|
Verma A, Mishra S. Spectrum of motor neuron diseases with HIV-1 infection. Ann Indian Acad Neurol 2006;9:103-9
| Introduction|| |
Motor neuron disease (MND) is a neurodegenerative disorder, characterized clinically by progressive weakness of limb, bulbar and respiratory muscles. No biological marker currently exists for the confirmatory diagnosis of MND. Clinically definite MND (El Escorial definite ALS) is characterized by the presence of mixed upper and lower motor neuron deficits in three or more anatomical areas. Patients with isolated upper motor neuron disorder (primary lateral sclerosis, PLS) or lower motor neuron disorder (progressive muscular atrophy, PMA) exhibit a relatively benign clinical course compared to that in classical MND. Although a defect in Cu/Zn superoxide dismutase 1 accounts for about 1% of all cases, the cause of sporadic MND remains unknown.
A viral etiology of MND has been hypothesized for over four decades. Because poliovirus selectively infects motor neurons in the brain stem and spinal cord, a persistent poliovirus infection as a cause of ALS was proposed in 1960s. It was demonstrated subsequently, that human T-cell lymphocytotropic virus type 1 (HTLV-1) also can cause a MND syndrome. Evidence of pyramidal tract, anterior horn cell involvement and lymphocytic inflammation has been reported at autopsy in cases of HTLV-1 myelopathy. Human foamy retrovirus has also been shown to cause MND in animals, although it is pathologically different from that of sporadic human MND.
Retroviral hypothesis of MND is particularly attractive, because retroviruses replicate by synthesizing and integrating a DNA copy that persists into the host genome.
HIV-associated MND was first reported in 1985, just 4 years after the initial description of AIDS. In the ensuing two decades, at least 22 additional cases of MND syndrome in association with HIV infection have been reported,,,,,,,,,,,,,,, [Table - 1]. Higher frequency of MND in HIV seropositive population and reports of slowing,,, arrest,, or occasional reversal, of motor deficit following antiretroviral therapy in these cases, have been proposed as evidence for the causal relation between the HIV infection and MND.
We describe HIV-associated MND in two patients and review the literature regarding MND with HIV infection, to compare and contrast this syndrome with the sporadic MND.
| Case Reports|| |
Case 1: A 57-year-old man was first hospitalized for Pneumocystis carini pneumonia in December 2001. Laboratory testing revealed that he was HIV seropositive by enzyme-linked immunosorbant assay and Western blot analysis. His CD 4 + T cell count was 80/mm 3 and HIV viral load was 180 x 10 3 copies per milliliter. Following recovery from pneumonia, he started antiretroviral therapy with zidovudine, lamivudine, lopinavir and ritonavir [Figure - 1]. In December 2001, he returned to work full-time.
In early 2003, he reported stiffness of his legs and difficulty in walking, followed a few months later, by slurred speech. Speech difficulty progressed gradually, although his gait abnormality remained stable. Over the ensuing year, he developed emotional lability. In mid 2004, parallel to his partially effective HAART regimen and improvement in plasma viral load and immune status, he noticed about 25% improvement in speech and hyper-emotionality. He was virtually asymptomatic in limbs at that time. In the later part of 2004, he showed worsening of his speech. In December 2004, his speech was approximately 50% comprehensible and emotional lability had progressed to a level that he began experiencing mild social disability at work and home. By March 2005, his CD 4 + T cell count was 488 and HIV viral load 1.6 x 10 3/ml. Following the addition of tenofovir to his antiretroviral regimen, plasma HIV became undetectable. In that year, he began low technology tools to supplement speech communication. He denied dysphagia, limb weakness, muscle twitching, cognitive dysfunction or sphincteric disturbance. His past medical history was unremarkable. There was no family history of neurological disorder.
In April 2005, he was a healthy-appearing man weighing 72 kg. Cognition and language were normal. He had a severe spastic dysarthria, most words were guttural sounding and produced slowly and monosyllabically. He could write legibly and accurately to verbal and written commands and read with normal comprehension. Verbal repetition was commensurate with the restricted motor speech output. Cranial nerve examination was normal, but his jaw jerk was brisk. Other than a positive snout reflex, there were no other frontal lobe release signs. A clasp-knife spasticity was noted in all extremities. Strength was normal in the upper extremities and 4+ (MRC, medical research council) in lower extremities. No atrophy or fasciculations were observed. Muscle stretch reflexes were exaggerated in all extremities with bilateral Hoffmann and Babinski signs and crossed adductors at knees. His gait was moderately spastic. Sensation to all modalites was normal and Romberg was negative.
Complete blood count and differentials, blood chemistry, thyroid function test, vitamin B 12 and folate levels, very long chain fatty acid levels, connective tissue disease screen and syphilis, Lyme, HTLV-1 and hepatitis serological tests, were all normal or negative. CSF analysis was not performed. Magnetic resonance imaging of the brain and cervical spine was normal. Fibroptic naso-pharyngo-laryngoscopy revealed no upper airway abnormalities. Electrophysiological studies performed in September 2005 showed normal motor unit morphology and decreased voluntary recruitment, consistent with upper motor neuron dysfunction. There was no evidence of denervation. Sensory and motor nerve conductions were normal.
Sertraline (100 mg/d) and baclofen (30 mg/d) initiated in June 2005 resulted in modest improvement in hyperemotionality and spasticity, but had no effect on his dysarthria. In November 2005, his verbal speech output was reduced to 5 - 10 words per minute and he began to use a computer-assisted speech generation device.
When last seen in February 2006, his spastic quadriparesis was stable [Figure - 1]. There were no cranial nerve deficits nor atrophy or fasciculations of the limb muscles. His most recent (January 2006) CD 4 + T cell count was 618/mm 3sub and plasma viral load undetectable. He continued to work full time as a driver and dispatcher.
Case 2: A 60-year-old homosexual man developed muscle twitching and progressive asymmetric muscle weakness and atrophy in lower extremities in October 2001. His case is reported in detail elsewhere. Briefly, he had known seropositivity for HIV since 1990. His motor symptoms progressed gradually and by June 2002, he had upper extremities and bulbar weakness. An EMG examination suggested diffuse and active neurogenic changes in tongue and limb muscles. When first seen at our Center in June 2002, he had moderate dysarthria and mild dysphagia, tongue atrophy and fasciculations and a positive jaw jerk and pout reflex. Examination of limbs showed asymmetric muscle atrophy and weakness and diffuse fasciculations. Jaw jerk and limb muscle stretch reflexes were exaggerated. Babinski was positive bilaterally. Coordination and sensory modalities were preserved. With mixed upper and lower motor neuron deficits in all limbs and in bulbar territory, a diagnosis of clinically definite ALS (El Escorial) was made.
A repeat EMG examination confirmed fasciculations and ongoing active neurogenic changes in three limb muscles. Sensory and motor nerve conductions were unremarkable. Brain magnetic resonance imaging scan (MRI) showed mild diffuse atrophy and spine MRI was normal. Lumbar spinal tap and CSF analysis showed 6 lymphocytes/ml, 54 mg/dl proteins and 65 mg/dl glucose. HIV load in CSF was not performed.
He had been receiving a combination antiretroviral therapy (zidovudine, lamivudine and saquinavir) since 1999 and the HIV RNA (PCR) in plasma was undetectable during this period of time. HIV genotype from his plasma sample had previously revealed drug sensitive HIV-1 strains. A CD4+ T cell count was 430/mm 3 and CD4+/CD8+ ratio at 0.77.
He continued with highly active antiretroviral therapy (HAART) and received Riluzole 50 mg twice a day. His weakness continued to progress, resulting in progressive disability over time. He died following respiratory failure in October 2002, 13 months after the onset of the ALS.
Review of cases of MND in HIV infection
During the last 20 years, 23 cases (male 18, female 5) of HIV-associated MND syndrome have been reported,,,,,,,,,,,,,,,, [Table - 1]. A majority (17 patients) of them had lower motor neuron predominant syndrome,,,,,,,,,,,,, and they can be categorized as El Escorial probable or possible ALS cases. The remainder of the 6 patients,, (case ),, had mixed upper and lower motor neuron deficits and fulfilled the El Escorial criteria for a definite ALS diagnosis. HIV-associated MND occurred in relatively younger age (range 22-61, mean 37.3 year) in these patients than those in patients with sporadic MND, in whom 75% of affected persons are between the ages of 55 and 84 years. There was no consistent relationship of MND syndrome to the duration of HIV infection or stage of the HIV disease [Table - 1].
Among HIV-associated MND cases that mirrored sporadic ALS, Hoffman et al described a limited follow up on a 26-year-old patient with advanced AIDS and rapidly progressive ALS. Moulignier et al retrospectively identified six cases of a rapidly progressive disorder resembling degenerative MND among 1700 patients with HIV infection, who were seen over a 13-year period. Only one patient (patient 1) met the El Escorial criteria for a definite ALS. The other five patients in the Moulingnier study were classified as having probable or possible ALS, but it was unclear how many were in each category. These cases differed from the patients with sporadic ALS in relatively younger age, more rapid progression of the motor deficit and at least partial clinical recovery following HAART. MacGowan et al reported HIV infection and ALS-like syndrome in a 32-year-old woman who demonstrated recovery of the motor deficit in tandem with resolution of brainstem white matter abnormalities, following the institution of antiretroviral therapy. The underlying pathology of this case was never determined and the basis of MND was unclear. Zoccolella et al described clinically definite ALS in a 44-year old man who also had HIV disease. The MND was progressive despite effective retroviral control on HAART and the patient died three years after the onset of motor symptoms. The authors concluded the incidental occurrence of HIV disease and MND in this patient. Verma et al recently described two patients with clinically definite ALS, in whom the clinical course of MND mirrored that of classical sporadic ALS. Of these 6 clinically definite ALS cases, two stabilized or improved, on HAART, three showed inexorable progression, while on HAART and one case occurred before the HAART era.
Isolated upper motor neuron syndrome (PLS) has not been previously reported in patients with HIV infection. Isolated lower motor neuron (PMA) involvement has been the most frequent occurrence in HIV-associated MND syndrome. Possible sites of involvement in isolated lower motor neuron syndrome could be anterior horn cells, perikaria or motor axons. Most patients with HIV disease and isolated lower motor neuron syndrome showed clinical or laboratory evidence of involvement outside the motor neuron pool and most who received HAART showed at least partial improvement [Table - 1]. Sinha et al reported a 37-year-old, HIV-infected man with a predominant lower motor neuron disorder and tuberculosis. The patient showed temporary improvement in motor deficit following antiretroviral and antitubercular therapy. Von Giesen et al commented on two male partners infected with the same HIV strain, but only one developed MND syndrome and his motor deficit progressed despite HAART. Berger et al described brachial amyotrophic diplegia, a focal variant of PMA, in a 35-year-old HIV-seropositive man; effective antiretroviral therapy stabilized the motor neuron deficit in this case.
Three pathological reports of HIV-associated MND syndrome have also been described.,, In one autopsy report, the clinical course of MND was atypical and the patient had shown improvement in motor deficit following antiretroviral therapy. Autopsy study revealed a combination of myeloradiculopathy and myopathy, without evidence of anterior horn cell disease. A combination of myopathy and myeloradiculopathy might have mimicked clinically, a limb-onset MND in this case. Autopsy in the second case showed evidence of AIDS encephalopathy, vacuolar myelopathy and motor and sensory neuronal loss. The pathology in third case, revealed motor neuron atrophy and sensory neuropathy.
| Discussion|| |
Virtually, any part of the central or peripheral nervous system can be affected in patients with HIV disease. MND syndrome can occur in several forms with HIV infection. A summary of previously reported 23 cases of MND in conjunction with HIV infection is included in the Table. In some cases,,,, HIV-associated MND may be indistinguishable from classical sporadic ALS, resulting in a progressive disorder of upper and lower motor neurons and culminating in progressive weakness, respiratory difficulty and death.,, More frequently however, HIV-associated MND is characterized by a variably progressive lower motor neuron disorder affecting limb or bulbar territory muscles, a clinical phenotype similar to the sporadic PMA. The third clinical phenotype of MND, namely PLS, with upper motor neuron disorder has not been previously reported in patients with HIV infection.
Our one patient (case 2) had clinical features of a definite MND and the clinical course of disease in him mirrored that in sporadic MND. Effective HAART failed to arrest or slow the disease progression. The clinical form and course of MND in this patient resembles that reported in other similar cases of HIV-associated definite MND., However, in contrast to other occasional reports,, we did not observe neurological recovery following effective HAART in this case. The causal relationship between HIV infection and MND remains uncertain in this case, but our suspicion is that it was a coincidental occurrence.
Our other patient (case 1) had features indicative of selective and symmetrical corticospinal tract degeneration, similar to that in PLS variant of sporadic MND. Severe spastic dysarthria in this case, suggested early and significant corticobulbar involvement. The motor deficit remained confined to the upper motor neuron over a follow-up period of 3 years. He had no clinical, laboratory or neuroimaging evidence of secondary central or peripheral nervous system disease. Electrophysiological investigations failed to reveal evidence of lower motor neuron involvement, even after several years of follow up in these cases. Therefore, we believe that isolated upper neuron syndrome involvement in this case is consistent with the pyramidal tract degeneration or PLS form of sporadic MND.
The gait dysfunction and brisk muscle stretch reflexes of HIV-associated dementia (HAD), may mimic that observed in motor neuron disorder. However, HAD is clinically defined by cognitive impairment and psychomotor slowing, features conspicuously absent in our patients. Furthermore, the corticobulbar tract involvement, absence of sensory or autonomic dysfunction, negative serologies for syphilis and HTLV 1 and normal spine neuroimaging report, militate against the diagnosis of HIV-associated vacuolar myelopathy or other infectious myelopathies. An etiological link between PLS and HIV remains a distinct possibility, although other explanations need to be considered.
MND or MND-mimic disease in a patient with HIV infection can theoretically occur as a consequence of direct viral infection of the motor neurons, indirect effect of HIV infection and inflammatory byproducts on motor neurons, an opportunistic infection secondary to immunosuppression or simply by coincidence. Reports of classical ALS in patients with HIV infection are distinctly rare, and their association may be fortuitous. In these cases, HIV infection preceded ALS by several years, the ALS symptoms began at a later age and their ALS deficit progressed inexorably despite effective HAART. In a recent report, indinavir therapy in sporadic ALS failed to alter the clinical course of the disease. Two cases reported by MacGowan et al and Moulignier et al (case 1) are exceptional, in that they both fulfilled criteria for a definite ALS diagnosis and showed improvement on HAART. However, the ages of these patients (32 and 27 years, respectively) and their rapid clinical worsening were atypical for classical ALS. One of these two cases also demonstrated white matter lesions of uncertain etiology in the brain stem; however, the coexistence of two or more neurological disorders in an AIDS patient is not unusual.
The majority of reported cases of HIV-associated MND syndrome,,,,,, (case 2 to 5 in [Table - 1]),,,,, can best be categorized under the rubric of El Escorial probable or possible ALS cases and they differ from classical sporadic ALS in a number of ways. First, they occurred in younger patients than is typical for classical ALS. Second, they were unusually rapidly progressive. Third, the disorder did not progress inexorably, but variably improved after instituting antiviral therapy. Finally, in the small number of pathologically studied cases, all showed evidence of inflammation in the CNS, which is typically absent in classical sporadic MND.
The mechanism of motor neuron demise in HIV-associated MND syndrome is unknown. HIV is not a neurotropic virus. It rarely, if ever, infects neurons, but infection occurs predominantly in microglial cells within the central nervous system. Primary neurological involvement in HIV infection is presumed to occur by neurotoxic viral proteins or by cytokines and chemokines, elaborated as a consequence of the HIV disease. Thus, the clinical improvement following antiretroviral therapy and the consequent viral suppression and CD 4 + T-cell elevation and immune reconstitution, suggest indirect effect of HIV infection in MND syndrome. Motor deficit related to the HIV-driven MND syndrome, similar to HIV-associated dementia, can potentially improve following effective HAART.
In summary, it appears that the full panoply of MND syndromes may occur with HIV infection. The clinical manifestations of HIV-associated MND syndrome include upper motor neuron, lower motor neuron or both upper and lower motor neuron disorder. MND syndrome with HIV infection generally differs from the classical sporadic ALS in a number of important ways. Although causal relationship between HIV infection and classical ALS is uncertain, the occasional stabilization or recovery following HAART, underscores the importance of recognition and treatment of the HIV-associated MND syndrome.
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[Figure - 1]
[Table - 1]
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