Case Report
Amyotrophic Lateral Sclerosis-Like Presentation in a HIV-Positive Patient
Journal of the International Association of Providers of AIDS Care 2014, Vol. 13(6) 515-518 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/2325957414535254 jiapac.sagepub.com
Kuljeet Singh Anand, MD, DM, Ankur Wadhwa, MD, Jyoti Garg, MD, DNB, DM, and Rakesh Kumar Mahajan, MD1
Abstract There has been several reports of an MND like syndrome in HIV-1 infection, however the data is still sparse. Furthermore, HIV-associated amyotrophic lateral sclerosis (ALS) syndrome differs from the classical ALS in some key aspects.. A 44-yearold male presented with a history of insidious onset and gradually progressive asymmetric weakness of lower limbs. He also complained of thinning in both legs, the left leg more than the right since 1 year along with spontaneous twitching of muscles in both the thighs. On neurological examination, the assessment of higher mental functions was normal. There were no cranial nerve deficits. Motor power was grade 5/5 (Medical Research Council scale) in both the upper limbs and 4þ at hips and knees bilaterally, 5 at right ankle, and 4þ at left ankle. All the deep tendon reflexes were brisk with extensor planter responses. There were no cerebellar signs or sensory deficits. HIV-1 was reactive in enzyme-linked immunosorbent assay. Electrophysiological studies were conducted per the MND protocol.None of the nerves studied showed an abnormal drop in compound muscle action potential amplitude with proximal stimulation. There was evidence of diffuse spontaneous activity, which manifests as fibrillation and fasciculation potentials in most muscles tested . Overall there seems to be sufficient evidence toimplicate HIV as a potential cause of an ALS-like disorder, but one must also consider the possibility of coincidental HIV infection in patients who have sporadic ALS. Keywords amyotrophic lateral sclerosis, HIV
The association of HIV and motor neuron disease (MND) was first reported in 1985, about 4 years after the initial description of AIDS.1 Although there has been several reports of an MNDlike syndrome in HIV-1 infection, the data on this are still sparse. Furthermore, HIV-associated amyorophic lateral sclerosis (ALS) syndrome differs from the classical ALS in some key aspects, including a younger age of presentation, subacute clinical progression, and the spread of pathology beyond the motor neuron system.2 Due to a paucity of data, a clear understanding of pathogenesis underlying ALS-like syndrome in HIV is still lacking, and the pattern of motor neuron vulnerability is not fully explained. Among the possible mechanisms that are considered include neuronal excitation and free radical generation.3 Clinicopathological studies of ALS suggest that the site of onset is the most severely affected, with outward spread to contiguous body regions and that the upper motor neuron (UMN) and lower motor neuron (LMN) loss occur independently of each other.4 Hence, HIV as a cause of ALS remains controversial. Here we report a 44-year-old male who presented with lower limb onset ALS-like syndrome and was subsequently detected to be seropositive for HIV-1 infection.
weakness started in the left lower limb with difficulty in getting up from squatting position and climbing stairs followed by slippage of slippers for the past 1½ years. It similarly progressed to involve the right lower limb over a period of 8 months. There was no weakness in the upper limbs. He also complained of thinning in both legs, the left leg more than the right for 1 year, with spontaneous twitching of muscles in both the thighs. There was no history suggestive of dysphagia, dysarthria, sensory loss, and bowel or bladder disturbances. There was no past medical history of neck pain, backache, or trauma. No other family member had a similar illness. He used to consume alcohol occasionally and denied unsafe sexual practices, intravenous substance abuse, or blood transfusion in the past. General physical examination revealed moderately built, poorly nourished patient with oral thrush and folliculitis over both the legs (Figure 1). On neurological examination, the assessment of higher mental functions including Mini-Mental
Case Report
Corresponding Author: Ankur Wadhwa, Block B-1B, House No. 1, 2nd Floor, Janakpuri, New Delhi 110058, India. Email: [email protected]
A 44-year-old male presented with a history of insidious onset and gradually progressive weakness of lower limbs. The
1
Department of Neurology and Microbiology, Dr R.M.L. Hospital, New Delhi, India
Downloaded from jia.sagepub.com at UNIV OF CONNECTICUT on May 10, 2015
516
Journal of the International Association of Providers of AIDS Care 13(6)
Figure 1. Folliculitis over both the legs of the patient.
Status Examination was normal. There were no cranial nerve deficits. Motor system examination revealed normal bulk in both upper limbs with wasting of both lower limbs, the left leg more than the right, including glutei, quadriceps, peronei, tibialis anterior and posterior, gastronemius, extensor digitorum brevis, and intrinsic foot muscles (Figures 2 and 3), and spasticity in both lower limbs. Prominent fasciculations were observed in bilateral quadricep muscles. Motor power was grade 5/5 (Medical Research Council scale) in both upper limbs, 4þ at the hips and knees bilaterally, 5 at right ankle, and 4þ at the left ankle. All the deep tendon reflexes were brisk with extensor planter responses. There were no cerebellar signs or sensory deficits. Gait was normal. Hematological investigations revealed hemoglobin (Hb) of 11.3 g%, total leukocyte count of 8500 cells/mm3, differential leukocyte count—neutrophils of 32%, lymphocytes of 65%, eosinophils of 03%, platelet count of 1.6 lakh/mm3, and erythrocyte sedimentation rate of 12 mm/h. Biochemical investigations showed serum sodium level was 140 mEq/L, serum potassium was 4.0 mEq/L, serum calcium was 8.1 mEq/L, fasting blood sugar was 83 mg%, creatine kinase was 88 U/L, and vitamin B12 was 394 pg/mL. Liver,
Figure 2. Wasting of the leg muscles, left more than right side.
renal, and thyroid function tests were within the normal limits. HIV-1 was reactive in enzyme-linked immunosorbent assay.
Figure 3. Wasting of the feet, left more than right side.
Downloaded from jia.sagepub.com at UNIV OF CONNECTICUT on May 10, 2015
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T-helper (CD4) absolute count was 98 cells/mm3, cerebrospinal fluid analysis cytology was 75 to 80 cells, lymphocytes, protein was 38 mg%, sugar was 58 mg%, and Gram stain, Ziehl-Neelsen stain, and India ink showed no organisms. Enzyme-linked immunosorbent assay for cytomegalovirus was nonreactive. Magnetic resonance imaging (MRI) of cervical and lumbosacral spine including chest x-ray was unremarkable. Electrophysiological studies were conducted per the MND protocol (nerve conduction velocity of all 4 limbs and electromyography [EMG] of both lower limbs and 1 upper limb including distal and proximal muscles, thoracic paraspinal, and tongue muscles). Nerve conduction velocity studies of lower limbs (tibial and peroneal) revealed normal motor and sensory nerve conduction with large amplitude, long duration, and polyphasic motor unit potentials. None of the nerves studied showed an abnormal drop in compound muscle action potential amplitude with proximal stimulation. There was evidence of diffuse spontaneous activity, which manifests as fibrillation and fasciculation potentials in most muscles tested in both lower extremities, along with decreased recruitment. Thoracic paraspinal muscles showed fibrillation potentials, whereas the tongue EMG was normal. Patient was started on antiretroviral treatment, but follow-up was not possible.
Discussion The pathogenesis of ALS-like syndrome in HIV-positive patients is debatable, but several proposed mechanisms for classical ALS-like neuronal excitation and free radical generation may also be operative in HIV-associated central nervous system disease. Until now, there have been only a few case reports of ALS-like presentation in HIV-infected patients, and most of them at best are probable or possible ALS. These cases differ from classical ALS in a number of ways. First, they occur in younger patients than is typical for classical ALS. Second, they were rapidly progressive. Third, many of these variably improved after instituting antiretroviral therapy. Ours was a middle-aged man who presented with onset in the lower limbs and was subsequently found to be seropositive for HIV-1. Generally in 75% to 80% of patients with classical ALS, the symptoms begin with limb involvement, while 20% to 25% of patients present with bulbar symptoms. For those with limb involvement at presentation, the frequency of upper limb versus lower limb involvement is approximately equal. Patients with upper limb onset have twice the likelihood for onset in the dominant arm compared with the nondominant arm. There is an equal likelihood for presentation in either lower extremity. Women have a greater frequency of bulbar (speech dysfunction) onset than that of men. These observations suggest a greater likelihood for network dismantling especially where there is a better developed, or more complex, cortical network. ‘‘Flail arm’’ ALS is a regional phenotypic variant with a predominantly symmetrical pattern of disease that remains confined for an extended period in the arms and is associated with a slower rate of disease progression. A similar regional
syndrome is recognized in the lower limbs, which is also characterized by the contralateral rather than rostral spread of weakness and variously described as ‘‘creeping paralysis’’— the pseudopolyneuritic variant or ‘‘flail leg’’ ALS.5 A retrospective review of 1700 cases of HIV-1-infected patients identified 6 cases presenting as a reversible ALS-like syndrome, representing a 27-fold increased risk of developing an ALSlike disorder in that particular HIV-1-infected patient population.6 Similar to our patient, these cases were somewhat younger than the normal ALS population, all but 1 being younger than 40 years at the time of diagnosis. Onset was characteristically in a monomelic pattern followed by a very rapid spread to other regions within weeks. There were clinical features of both UMN and LMN involvement, with fasciculations, cramps, and bulbar symptoms. Unlike ours, 2 patients also had rapidly progressive dementia, with other features suggesting an additional diagnosis of AIDS-dementia complex. MacGowan et al7 reported HIV infection and ALS-like syndrome in a 32-year-old woman who demonstrated recovery of motor deficit following antiretroviral therapy (ART).6 Curiously, this patient’s MRI showed white matter abnormalities in the brain stem, which also resolved after therapy and clinical recovery. In another case report, Sinha et al2 studied a 37-year-old HIV-infected man with a predominant LMN disorder and tuberculosis. The patient showed temporary improvement in motor deficit following ART and antitubercular therapy. Von Giesen et al8 reported 2 male partners infected with the same HIV-1 strain but only 1 developed ALS-like syndrome and his motor deficit progressed despite treatment.7 Overall, there seems to be sufficient evidence to implicate HIV as a potential cause of an ALS-like disorder, but one must also consider the possibility of coincidental HIV infection in patients who have sporadic ALS. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Hoffman PM, Festoff BW, Giron LT Jr, Hollenbeck LC, Garruto RM, Ruscetti FW. Isolation of LAV/HTLV-III from a patient with amyotrophic lateral sclerosis. N Eng J Med. 1985;313(5): 324-325. 2. Sinha S, Mathews T, Arunodaya GR, et al. HIV-1 clade-Cassociated ‘ALS’-like disorder: first report from India. J Neurol Sci. 2004;224(1-2):97-100. 3. Bromberg MB. Pathogenesis of amyotrophic lateral sclerosis: a critical review. Curr Opin Neurol. 1999;12(5):581-588. 4. Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology. 2009;73(10):805-811.
Downloaded from jia.sagepub.com at UNIV OF CONNECTICUT on May 10, 2015
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Journal of the International Association of Providers of AIDS Care 13(6)
5. Wijesekera LC, Mathers S, Talman P, et al. Natural history and clinical features of the flail arm and flail leg ALS variants. Neurology. 2009;72(12):1087-1094. 6. Moulignier A, Moulonguet A, Pialoux G, Rozenbaum W. Reversible ALS-like disorder in HIV infection. Neurology. 2001;57(6): 995-1001.
7. MacGowan DJ, Scelsa SN, Waldron M. An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology. 2001;57(6):1094-1097. 8. Von Giesen HJ, Kaiser R, Koller H, Wetzel K, Arendt G. Reversible ALS-like disorder in HIV infection. Neurology. 2002;59(3):474.
Downloaded from jia.sagepub.com at UNIV OF CONNECTICUT on May 10, 2015
Amyotrophic Lateral Sclerosis-Like Presentation in a HIV-Positive Patient
Journal of the International Association of Providers of AIDS Care 2014, Vol. 13(6) 515-518 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/2325957414535254 jiapac.sagepub.com
Kuljeet Singh Anand, MD, DM, Ankur Wadhwa, MD, Jyoti Garg, MD, DNB, DM, and Rakesh Kumar Mahajan, MD1
Abstract There has been several reports of an MND like syndrome in HIV-1 infection, however the data is still sparse. Furthermore, HIV-associated amyotrophic lateral sclerosis (ALS) syndrome differs from the classical ALS in some key aspects.. A 44-yearold male presented with a history of insidious onset and gradually progressive asymmetric weakness of lower limbs. He also complained of thinning in both legs, the left leg more than the right since 1 year along with spontaneous twitching of muscles in both the thighs. On neurological examination, the assessment of higher mental functions was normal. There were no cranial nerve deficits. Motor power was grade 5/5 (Medical Research Council scale) in both the upper limbs and 4þ at hips and knees bilaterally, 5 at right ankle, and 4þ at left ankle. All the deep tendon reflexes were brisk with extensor planter responses. There were no cerebellar signs or sensory deficits. HIV-1 was reactive in enzyme-linked immunosorbent assay. Electrophysiological studies were conducted per the MND protocol.None of the nerves studied showed an abnormal drop in compound muscle action potential amplitude with proximal stimulation. There was evidence of diffuse spontaneous activity, which manifests as fibrillation and fasciculation potentials in most muscles tested . Overall there seems to be sufficient evidence toimplicate HIV as a potential cause of an ALS-like disorder, but one must also consider the possibility of coincidental HIV infection in patients who have sporadic ALS. Keywords amyotrophic lateral sclerosis, HIV
The association of HIV and motor neuron disease (MND) was first reported in 1985, about 4 years after the initial description of AIDS.1 Although there has been several reports of an MNDlike syndrome in HIV-1 infection, the data on this are still sparse. Furthermore, HIV-associated amyorophic lateral sclerosis (ALS) syndrome differs from the classical ALS in some key aspects, including a younger age of presentation, subacute clinical progression, and the spread of pathology beyond the motor neuron system.2 Due to a paucity of data, a clear understanding of pathogenesis underlying ALS-like syndrome in HIV is still lacking, and the pattern of motor neuron vulnerability is not fully explained. Among the possible mechanisms that are considered include neuronal excitation and free radical generation.3 Clinicopathological studies of ALS suggest that the site of onset is the most severely affected, with outward spread to contiguous body regions and that the upper motor neuron (UMN) and lower motor neuron (LMN) loss occur independently of each other.4 Hence, HIV as a cause of ALS remains controversial. Here we report a 44-year-old male who presented with lower limb onset ALS-like syndrome and was subsequently detected to be seropositive for HIV-1 infection.
weakness started in the left lower limb with difficulty in getting up from squatting position and climbing stairs followed by slippage of slippers for the past 1½ years. It similarly progressed to involve the right lower limb over a period of 8 months. There was no weakness in the upper limbs. He also complained of thinning in both legs, the left leg more than the right for 1 year, with spontaneous twitching of muscles in both the thighs. There was no history suggestive of dysphagia, dysarthria, sensory loss, and bowel or bladder disturbances. There was no past medical history of neck pain, backache, or trauma. No other family member had a similar illness. He used to consume alcohol occasionally and denied unsafe sexual practices, intravenous substance abuse, or blood transfusion in the past. General physical examination revealed moderately built, poorly nourished patient with oral thrush and folliculitis over both the legs (Figure 1). On neurological examination, the assessment of higher mental functions including Mini-Mental
Case Report
Corresponding Author: Ankur Wadhwa, Block B-1B, House No. 1, 2nd Floor, Janakpuri, New Delhi 110058, India. Email: [email protected]
A 44-year-old male presented with a history of insidious onset and gradually progressive weakness of lower limbs. The
1
Department of Neurology and Microbiology, Dr R.M.L. Hospital, New Delhi, India
Downloaded from jia.sagepub.com at UNIV OF CONNECTICUT on May 10, 2015
516
Journal of the International Association of Providers of AIDS Care 13(6)
Figure 1. Folliculitis over both the legs of the patient.
Status Examination was normal. There were no cranial nerve deficits. Motor system examination revealed normal bulk in both upper limbs with wasting of both lower limbs, the left leg more than the right, including glutei, quadriceps, peronei, tibialis anterior and posterior, gastronemius, extensor digitorum brevis, and intrinsic foot muscles (Figures 2 and 3), and spasticity in both lower limbs. Prominent fasciculations were observed in bilateral quadricep muscles. Motor power was grade 5/5 (Medical Research Council scale) in both upper limbs, 4þ at the hips and knees bilaterally, 5 at right ankle, and 4þ at the left ankle. All the deep tendon reflexes were brisk with extensor planter responses. There were no cerebellar signs or sensory deficits. Gait was normal. Hematological investigations revealed hemoglobin (Hb) of 11.3 g%, total leukocyte count of 8500 cells/mm3, differential leukocyte count—neutrophils of 32%, lymphocytes of 65%, eosinophils of 03%, platelet count of 1.6 lakh/mm3, and erythrocyte sedimentation rate of 12 mm/h. Biochemical investigations showed serum sodium level was 140 mEq/L, serum potassium was 4.0 mEq/L, serum calcium was 8.1 mEq/L, fasting blood sugar was 83 mg%, creatine kinase was 88 U/L, and vitamin B12 was 394 pg/mL. Liver,
Figure 2. Wasting of the leg muscles, left more than right side.
renal, and thyroid function tests were within the normal limits. HIV-1 was reactive in enzyme-linked immunosorbent assay.
Figure 3. Wasting of the feet, left more than right side.
Downloaded from jia.sagepub.com at UNIV OF CONNECTICUT on May 10, 2015
Anand et al
517
T-helper (CD4) absolute count was 98 cells/mm3, cerebrospinal fluid analysis cytology was 75 to 80 cells, lymphocytes, protein was 38 mg%, sugar was 58 mg%, and Gram stain, Ziehl-Neelsen stain, and India ink showed no organisms. Enzyme-linked immunosorbent assay for cytomegalovirus was nonreactive. Magnetic resonance imaging (MRI) of cervical and lumbosacral spine including chest x-ray was unremarkable. Electrophysiological studies were conducted per the MND protocol (nerve conduction velocity of all 4 limbs and electromyography [EMG] of both lower limbs and 1 upper limb including distal and proximal muscles, thoracic paraspinal, and tongue muscles). Nerve conduction velocity studies of lower limbs (tibial and peroneal) revealed normal motor and sensory nerve conduction with large amplitude, long duration, and polyphasic motor unit potentials. None of the nerves studied showed an abnormal drop in compound muscle action potential amplitude with proximal stimulation. There was evidence of diffuse spontaneous activity, which manifests as fibrillation and fasciculation potentials in most muscles tested in both lower extremities, along with decreased recruitment. Thoracic paraspinal muscles showed fibrillation potentials, whereas the tongue EMG was normal. Patient was started on antiretroviral treatment, but follow-up was not possible.
Discussion The pathogenesis of ALS-like syndrome in HIV-positive patients is debatable, but several proposed mechanisms for classical ALS-like neuronal excitation and free radical generation may also be operative in HIV-associated central nervous system disease. Until now, there have been only a few case reports of ALS-like presentation in HIV-infected patients, and most of them at best are probable or possible ALS. These cases differ from classical ALS in a number of ways. First, they occur in younger patients than is typical for classical ALS. Second, they were rapidly progressive. Third, many of these variably improved after instituting antiretroviral therapy. Ours was a middle-aged man who presented with onset in the lower limbs and was subsequently found to be seropositive for HIV-1. Generally in 75% to 80% of patients with classical ALS, the symptoms begin with limb involvement, while 20% to 25% of patients present with bulbar symptoms. For those with limb involvement at presentation, the frequency of upper limb versus lower limb involvement is approximately equal. Patients with upper limb onset have twice the likelihood for onset in the dominant arm compared with the nondominant arm. There is an equal likelihood for presentation in either lower extremity. Women have a greater frequency of bulbar (speech dysfunction) onset than that of men. These observations suggest a greater likelihood for network dismantling especially where there is a better developed, or more complex, cortical network. ‘‘Flail arm’’ ALS is a regional phenotypic variant with a predominantly symmetrical pattern of disease that remains confined for an extended period in the arms and is associated with a slower rate of disease progression. A similar regional
syndrome is recognized in the lower limbs, which is also characterized by the contralateral rather than rostral spread of weakness and variously described as ‘‘creeping paralysis’’— the pseudopolyneuritic variant or ‘‘flail leg’’ ALS.5 A retrospective review of 1700 cases of HIV-1-infected patients identified 6 cases presenting as a reversible ALS-like syndrome, representing a 27-fold increased risk of developing an ALSlike disorder in that particular HIV-1-infected patient population.6 Similar to our patient, these cases were somewhat younger than the normal ALS population, all but 1 being younger than 40 years at the time of diagnosis. Onset was characteristically in a monomelic pattern followed by a very rapid spread to other regions within weeks. There were clinical features of both UMN and LMN involvement, with fasciculations, cramps, and bulbar symptoms. Unlike ours, 2 patients also had rapidly progressive dementia, with other features suggesting an additional diagnosis of AIDS-dementia complex. MacGowan et al7 reported HIV infection and ALS-like syndrome in a 32-year-old woman who demonstrated recovery of motor deficit following antiretroviral therapy (ART).6 Curiously, this patient’s MRI showed white matter abnormalities in the brain stem, which also resolved after therapy and clinical recovery. In another case report, Sinha et al2 studied a 37-year-old HIV-infected man with a predominant LMN disorder and tuberculosis. The patient showed temporary improvement in motor deficit following ART and antitubercular therapy. Von Giesen et al8 reported 2 male partners infected with the same HIV-1 strain but only 1 developed ALS-like syndrome and his motor deficit progressed despite treatment.7 Overall, there seems to be sufficient evidence to implicate HIV as a potential cause of an ALS-like disorder, but one must also consider the possibility of coincidental HIV infection in patients who have sporadic ALS. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Hoffman PM, Festoff BW, Giron LT Jr, Hollenbeck LC, Garruto RM, Ruscetti FW. Isolation of LAV/HTLV-III from a patient with amyotrophic lateral sclerosis. N Eng J Med. 1985;313(5): 324-325. 2. Sinha S, Mathews T, Arunodaya GR, et al. HIV-1 clade-Cassociated ‘ALS’-like disorder: first report from India. J Neurol Sci. 2004;224(1-2):97-100. 3. Bromberg MB. Pathogenesis of amyotrophic lateral sclerosis: a critical review. Curr Opin Neurol. 1999;12(5):581-588. 4. Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology. 2009;73(10):805-811.
Downloaded from jia.sagepub.com at UNIV OF CONNECTICUT on May 10, 2015
518
Journal of the International Association of Providers of AIDS Care 13(6)
5. Wijesekera LC, Mathers S, Talman P, et al. Natural history and clinical features of the flail arm and flail leg ALS variants. Neurology. 2009;72(12):1087-1094. 6. Moulignier A, Moulonguet A, Pialoux G, Rozenbaum W. Reversible ALS-like disorder in HIV infection. Neurology. 2001;57(6): 995-1001.
7. MacGowan DJ, Scelsa SN, Waldron M. An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology. 2001;57(6):1094-1097. 8. Von Giesen HJ, Kaiser R, Koller H, Wetzel K, Arendt G. Reversible ALS-like disorder in HIV infection. Neurology. 2002;59(3):474.
Downloaded from jia.sagepub.com at UNIV OF CONNECTICUT on May 10, 2015
