ALS syndrome in patients with HIV-1 infection

doi:10.1016/j.jns.2005.09.005

Journal of the Neurological Sciences

Volume 240, Issues 1–2, 15 January 2006, Pages 59-64

https://doi.org/10.1016/j.jns.2005.09.005 Get rights and content

Abstract

Background

A viral etiology of amyotrophic lateral sclerosis (ALS) has been proposed because of the selective vulnerability of motor neurons to certain viruses. During the last 20 years, at least 19 cases of ALS or ALS-like disease have been reported in HIV-1 (HIV) seropositive individuals.

Objective

To describe two cases of clinically definite ALS in patients with HIV infection and to review the previously reported cases of HIV-associated ALS syndrome.

Setting

A multidisciplinary ALS center and Neuro-AIDS clinic at a tertiary care university hospital.

Patients/Design

We investigated and prospectively monitored two patients who had developed clinically definite ALS by El Escorial criteria several years after acquiring the HIV infection. The previously reported cases of ALS or ALS-like disease in patients with HIV infection were reviewed for comparison and contrast with the characteristics of sporadic ALS.

Results

The clinical course of ALS in our two HIV seropositive individuals mirrored that of classical sporadic ALS. A review of previously described 19 patients with ALS syndrome revealed clinically definite ALS in 4 cases and clinically probable or possible ALS in 15. ALS commenced at different stages of the HIV disease; in 7 patients, HIV infection was discovered contemporaneously with diagnosis of ALS. CD4⁺ T cell count ranged from 2 to 560 cells/mm³. Three (1 definite ALS) of the fatal cases were studied at autopsy and all exhibited pathology outside the motor neuron pool. Unlike our patients, 7 of 8 patients with HIV-associated ALS syndrome receiving HAART demonstrated at least partial recovery of their motor deficit.

Conclusions

ALS-like syndrome can occur in association with HIV infection; however, the causal relationship remains uncertain. Patients with ALS syndrome related to HIV infection are generally younger in age and often demonstrate pathology outside the motor neuron system. Patients with HIV-associated ALS syndrome may improve following antiretroviral therapy. An aggressive HAART regimen to reduce viral load should be pursued in all such cases.

Introduction

The cause of sporadic amyotrophic lateral sclerosis (ALS) is unknown. A viral etiology of ALS has been hypothesized for over four decades. Because poliovirus selectively infects motor neurons, in 1960s and 1970s a persistent poliovirus infection was proposed as a possible cause of ALS [1]. Subsequent authors implicated [2] or refuted [3] other enteroviruses to cause ALS. In 1980s, it was reported that human T-cell lymphotropic virus type I (HTLV-1) causes an ALS syndrome [4]. Evidence of pyramidal tract and anterior horn cell involvement and lymphocytic inflammation has been reported at autopsy in cases of HTLV-1 myelopathy [5]. Human foamy retrovirus is known to cause motor neuron disease in mice [6], but this illness is pathologically different from human ALS [7].

Over the last 20 years, at least 19 cases of ALS or ALS-like disease (ALS syndrome) in association with human immunodeficiency virus type 1 (HIV) infection have been reported [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]. Additionally, other forms of motor neuron disease, such as, brachial amyotrophic diplegia, have also been seen with this infection [22]. Higher frequency of ALS syndrome in HIV seropositive population [16] and reports of slowing [17], [19], [21], arrest ([13], [16] (case 1)), or occasional reversal ([15], [16] (cases 2 and 6)) of motor deficit following antiretroviral therapy in these cases have been proposed as evidence for the causal relationship between the HIV infection and ALS. Retrovirus hypothesis of ALS is inherently attractive because retroviruses replicate by synthesizing and integrating a DNA copy that persists into the host's genome. However, HIV is not known to infect motor neurons. Furthermore, HIV-associated ALS syndrome differs from classical ALS in some key respects, including a younger age, subacute clinical progression, and spread of pathology beyond the motor neuron system [8], [9], [10], [11], [12], [14], [15], [16], [21]. Thus, authors in past have favored [15], [16] or questioned [18] the causal relationship between the HIV infection and ALS syndrome. The HIV cause of classical ALS currently remains controversial.

We report two patients with HIV infection and clinically definite ALS (El Escorial) [23] from among our cohorts of patients at a large ALS care center and Neuro-AIDS clinic and comment on the HIV-associated ALS syndrome.

Section snippets

Case 1

A 60-year-old homosexual man developed muscle twitching and progressive asymmetric muscle weakness and atrophy in lower extremities in October 2001. He had known seropositivity for HIV since 1990 and his past medical history also included hypertension, gout, and a depressive disorder. His motor symptoms progressed gradually and by June 2002, he had upper extremities and bulbar weakness. An EMG examination elsewhere suggested diffuse and active neurogenic changes in tongue and limb muscles. When

Review of cases of ALS syndrome in patients with HIV infection

During the last 20 years, 19 cases (male 16, female 3) of HIV-associated ALS syndrome have been reported [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21] (Table 1). Four of these cases ([8], [15], [16] (case 1), [18]) fulfilled the El Escorial [23] criteria for clinically definite ALS and the remainder [9], [11], [12], [13], [14], [17], [19], [20], [21] were clinically probable or possible cases of ALS. HIV-associated ALS occurred in relatively younger age (range

Comments

ALS or ALS-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.

Most reported cases ([9], [10], [11], [12], [13], [14], [16] (case 2 to 5), [17], [19], [20], [21]) of HIV-associated ALS syndrome at best are probable or possible ALS cases and they differ

Acknowledgements

Presented in part at the 15th International ALS/MND Symposium, Philadelphia, December 2–4, 2004. The authors thank Ginna Gonzalez, RN and Graciela Reyes, RN for their help in clinical care of patients.

References (28)

Y. Kuroda et al.
Autopsy report of HTLV-I-associated myelopathy presenting with ALS-like manifestations
J Neurol Sci
(1991)
S. Sinha et al.
HIV-1 clade-C-associated “ALS”-like disorder: first report from India
J Neurol Sci
(2004)
D.C. Poskanzer et al.
The frequency of preceding poliomyelitis in amyotrophic lateral sclerosis
C.J. Woodall et al.
Sequences specific for enteroviruses detected in spinal cord from patients with MND
BMJ
(1994)
M.P. Walker et al.
Absence of echovirus sequences in brain and spinal cord of amyotrophic lateral sclerosis patients
Ann Neurol
(2001)
B. Jubelt
Viruses and motor neuron diseases
Adv Neurol
(1991)
A. Aguzzi et al.
Brain Pathol
(1992)
M.B. Gardner et al.
A spontaneous lower motor neuron disease apparently caused by indigenous type-C RNA virus in wild mice
J Nat Cancer Inst
(1973)
P.M. Hoffman et al.
Isolation of LAV/HTLV-III from a patient with amyotrophic lateral sclerosis
N Eng J Med
(1985)
J.H. Sher et al.
Motor neuron disease associated with AIDS
J Neuropathol Exp Neurol
(1988)

R.K. Verma et al.

HIV-related neuromuscular syndrome simulating motor neuron disease

Neurology

(1990)

P.P. Huang et al.

Lower motor neuron dysfunction associated with human immunodeficiency virus infection

Arch Neurol

(1993)

I. Casado et al.

Motor neuron disease and HIV

Rev Neurol

(1997)

D.M. Simpson et al.

Motor neuron disease associated with HIV-1 and anti-asialo GM1 antibody

Muscle Nerve

(1994)

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ALS syndrome in patients with HIV-1 infection

Abstract

Background

Objective

Setting

Patients/Design

Results

Conclusions

Introduction

Section snippets

Case 1

Review of cases of ALS syndrome in patients with HIV infection

Comments

Acknowledgements

J Neurol Sci

J Neurol Sci

The frequency of preceding poliomyelitis in amyotrophic lateral sclerosis

Sequences specific for enteroviruses detected in spinal cord from patients with MND

BMJ

Absence of echovirus sequences in brain and spinal cord of amyotrophic lateral sclerosis patients

Ann Neurol

Viruses and motor neuron diseases

Adv Neurol

Brain Pathol

A spontaneous lower motor neuron disease apparently caused by indigenous type-C RNA virus in wild mice

J Nat Cancer Inst

Isolation of LAV/HTLV-III from a patient with amyotrophic lateral sclerosis

N Eng J Med

Motor neuron disease associated with AIDS

J Neuropathol Exp Neurol