Motor Neuron Disease and Acquired Axonal ...

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Motor Neuron Disease and Acquired Axonal Neuropathy Association in HIV Infection: Case Report and Update Marco Orsini1,2, Marcos RG de Freitas, Julio Guilherme Silva2,12, Márzia Puccioni Sohler4, Carlos Henrique Melo Reis1, Antonio Marcos da Silva Catharino, Acary Bulle Oliveira6, Sérgio Machado7,13, Antonio Egidio Nardi7, Peter Salem1, Flavio Sztajnbok8, Marco AA Leite1, Cristiane Nascimento9, Eduardo Davidovich1, Fábio Henrique de Gobbi Porto10, Márcia Waddington Cruz11, Sara Lúcia Silveira de Menezes2 and Oscar Arias-Carrión3 Neurology Department, Antonio Pedro University Hospital, Federal Fluminense University; Rio de Janeiro, Brazil and Hospital Geral de Nova Iguaçu, Nova Iguaçu, Brazil; 2 Master Program of Science Rehabilitation (UNISUAM), Rio de Janeiro, Brazil; 3Movement Disorders and Transcraneal Magnetic Stimulation Unit, Hospital General Dr. Manuel Gea González, Secretaría de Salud, México D.F., México; 4Cerebrospinal Fluid, Clementino Fraga Filho Hospital of Federal University of Rio de Janeiro; Brazil; 6Neurology Department, São Paulo Federal University (UNIFESP), São Paulo, Brazil; 7Laboratory of Panic and Respiration, Institute of Psychiatry of Federal University of Rio de Janeiro (IPUB/UFRJ), Rio de Janeiro, Brazil; National Institute for Translational Medicine (INCT-TM); 8Rheumatology Department (UERJ), Rio de Janeiro, Brazil; 9Servidores Hospital of the State of Rio de Janeiro; 10Behavioral and Cognitive Neurology Unit, Department of Neurology, and Cognitive Disorders Reference Center (CEREDIC), Hospital das Clínicas of the University of São Paulo, São Paulo, Brazil; 11Neurophisiology, Rio de Janeiro Federal University (UFRJ); 12Physical Therapy Department, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil; 13 Physical Activity Sciences Postgraduate Program - Salgado de Oliveira University, Niterói, Brazil; Quiropraxia Program of Faculty of Medical Sciences, Central University (UCEN), Santiago, Chile; Institute of Philosophy of Federal University of Uberlândia, Minas Gerais, Brazil Abstract: Background: A possible viral etiology has been documented in the genesis of motor neuron disorders and acquired peripheral neuropathies, mainly due to the vulnerability of peripheral nerves and the anterior horn to certain viruses. In recent years, several reports show association of HIV infection with Amyotrophic Lateral Sclerosis – Syndrome, Motor Neuron Diseases and peripheral neuropathies. Objective: To report a case of an association between Motor Neuron Disease and Acquired Axonal neuropathy in HIV infection, and describe the findings of neurological examination, cerebrospinal fluid, neuroimaging and electrophysiology. Methods: The patient underwent through neurological examination. General medical examinations were performed, including, specific neuromuscular tests, analysis of cerebrospinal fluid, muscle biopsy and imaging studies. Results and Discussion: The initial clinical presentation of our case was marked by cramps and fasciculations with posterior distal paresis and atrophy in the left arm. We found electromyography tracings with deficits in the anterior horn of the spinal cord and peripheral nerves. Dysphagia and release of primitive reflexes were also identified. At the same time, the patient was informed to be HIV positive with high viral load. He received antiretroviral therapy, with load control but with no clinical remission. Conclusion: Motor Neuron disorders and peripheral neuropathy may occur in association with HIV infection. However, a causal relationship remains uncertain. It is noteworthy that the antiretroviral regimen may be implicated in some cases.

Keywords: Motor neuron disease, HIV infection, acquired neuropathies. INTRODUCTION In the era of of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV) infectionassociated morbidity and mortality have reduced drastically. Despite that, the prevalence of HIV-related peripheral and *Address correspondence to this author at the Rua Gastão Ruch 16|1402, 24220100, Niterói, Brazil; Tel: ????????????????????; Fax: ????????????????????; E-mail: [email protected] 1570-162X/12 $58.00+.00

central nervous system disorders remains stable. While some neurologic disorders related to immunosuppression induced by HIV, such as neurotoxoplasmosis, cryptococcal meningitis and CNS lymphoma, decreased in parallel; other manifestations do not show the same trend. Furthermore, after the introduction of HAART, the patient’s quality of life increased. However, chronic complications have arisen in some patients, leading to many motor and sensory disabilities: for instance, mononeuropathies, inflammatory demyelinating polyneuropathies, motor neuron disease, © 2012 Bentham Science Publishers

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polymyositis, myopathies, diffuse infiltrative lymphocytosis syndrome, mononeuritis multiplex and other clinical manifestations [1-3]. Peripheral neuropathy is the most common peripheral nervous system (PNS) disorder in HIV patients. The prevalence of neuropathy among HIV patients has been derived from a systematic review of 25 studies recently conducted by Ghosh et al. [4]. This systematic review showed a prevalence varying from 1.2% to 69.4%. Distal symmetric sensory polyneuropathy (DSP) affects up to one third of HIV patients. In addition, cases of motor neuron disease (MND) such as Amyotrophic Lateral Sclerosis (Amyotrophic lateral sclerosis; ALS)-like pseudobulbar palsy and many types of lower MNDs have been reported in HIV-1 seropositive patients [2, 5]. Nevertheless, the causal relationship between HIV-1/HIV-2 infection and (ALS)-like syndrome is still uncertain. The syndrome usually manifests itself as an LMN syndrome, especially in young patients [5]. Different forms of MND and peripheral neuropathy (PN), isolated or in association, may occur in HIV infected patients. In this report, we describe the clinical picture of a middle-aged man infected by HIV with both MND (ALSlike) and PN. We also discuss neurologic and complementary exams with a short review of the literature about this unusual association. CASE REPORT A 56-year-old engineer presented complaints of muscle cramps and myofasciculations during the last four years. The symptoms were initially located along the distal portion of the left arm, with subsequent progression to the entire arm. Moreover, he began to present emotional problems. After a few months, he manifested atrophy and weakness in his left hand, loss of dexterity and difficulties to move his fingers. At the same time, in September 2007, he was diagnosed with HIV. He had a CD4 cell count of 300 cells/ml and a viral load of 698 copies/ml. Anti-retroviral treatment was started and after three consecutive months of uninterrupted treatment, the viral load became undetectable. Despite this reduction of viral load, he presented clinical worsening, with more intense weakness and atrophy in his upper left limb. In addition, he began to present speech impairment. Neurologic examination showed weakness and atrophy in the upper left limb muscles (Table 1). There was severe atrophy in his left hand, developing into a so-called “cadaveric hand” (Fig. 1). Nevertheless, muscle power was normal in the lower limbs. Deep tendon reflexes were considered normal in all four limbs. Bilateral palmomentonian and mandibular reflexes were detected. Superficial and deep sensibilities were normal, as well as those of cranial nerve. In spite of the presence of dysphonia, there were no fasciculations or atrophy in the tongue. There were no signs of pyramidal tract dysfunction. The nerve conduction studies (NCS) revealed abolishment of sensory nerve action potential (SNAP) in both sural and superficial peroneal nerves. Median and ulnar SNAP latencies were normal with borderline amplitudes. The amplitude of compound motor action potential (CMAP)

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was reduced in left median and right ulnar nerves. The F wave was abolished in the ulnar and median nerves. The motor nerve conduction velocity was slightly reduced in the ulnar and median nerves (Tables 2 and 3). The electromyography (EMG) showed fibrillation potentials, positive sharp waves and neurogenic motor unit action potentials (MUAPs) in distal muscles of the upper limbs (Tables 4 and 5). Fasciculation potentials were observed only in the left deltoid muscle. Table 1.

Strength Grade Evaluation – Medical Research Council – MRC [6]

Key Muscle

Strenght Grade Left Limb

Right Limb

Deltóide

4

5

Biceps Brachii

3

5

Triceps Brachii

4

5

Braquiorradialis

3

5

Extensor Carpi Radialis

3

5

Fingers Flexors

3

5

Dorsal And Palmar Interosseous

2

5

Iliopsoas

5

5

Quadriceps Femoris

5

5

Tibialis Anterior

5

5

Extensor Hallucis Longus

5

5

Ankle Plantar Flexors

5

5

Fig. (1). Cadaveric hand.

A sural nerve biopsy was performed. In hematoxylin and eosin staining, the endo- and epineural vessels revealed thickening of their walls. Gomori thricome showed some fibrosis. In toluidine-blue staining, there were images of slight loss of fibers and thin myelin, suggesting remyelization and mainly chronic axonal degeneration. Spinal cord MRI demonstrated small, discreet cervical disc protrusions.

Motor Neuron Disease and Acquired Axonal Neuropathy Association in HIV Infection

Table 2.

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Motor Nerve Conduction Studies Nerve

Side

Latency (ms)

Amplitude (mV)

MCV (m\s)

Median

R

3.2

5.1 (distal) - 3.5 (proximal)

52

Median

L

4.3

0.6 (distal) – 0.4 ( proximal)

50

Ulnar

R

3.0

2.3 (distal) – 2.1 ( proximal)

50.1

Ulnar

L

2.9

5.5 (distal) – 5.8 (proximal)

61.3

Fibular

R

3.9


42.6

Fibular

L

4.4


41.3

Tibial

R

4.7

3.8 (distal: abdutor hálux)

NA

Tibial

L

5.1

4.1 (distal: abdutor hálux)

NA

Legend: NA (Not available). L: Left; R: Right. * MCV (Motor conduction velocity).

Table 3.

Sensory Nerve Conduction Studies Nerve

Side

Latency (ms)

Amplitude (μV)

SCV (m\s)

Median

R

2.6

11

38.1

Median

L

2.7

13

36.7

Ulnar

R

2.5

10

38.7

Ulnar

L

2.8

7

39.2

Superficial Fibular

R

0

0

0

Superficial Fibular

L

0

0

0

Sural

R

0

0

0

Sural

L

0

0

0

Legend: L: Left; R: Right. * SCV (sensory conduction velocity).

Table 4.

Electroneuromyography of the Upper Limbs (ENMG) Muscle

Side

Insertional Activity

Rest Activity

Recruitment Pattern

Deltoid

R

Normal

Positive sharp waves: 0 Fibrillation: 0 Fasciculation: 0

Neurogenic

Deltoid

L

Normal

Positive sharp waves: 0 Fibrillation: 0 Fasciculation: +++

Neurogenic

Radial carpal extensor

R

Normal

Positive sharp waves: +++ Fibrillation: +++ Fasciculation: 0

Neurogenic

Radial carpal extensor

L

Normal

Positive sharp waves: +++ Fibrillation: ++ Fasciculation: 0

Neurogenic

Common extensor muscle of fingers

R

Normal


Normal

Common extensor muscle of fingers

L

Normal

Positive sharp waves: 0 Fibrillation: +++ Fasciculation: 0

Normal

First palmar interosseous muscle

R

Normal

Positive sharp waves: 0 Fibrillation: ++ Fasciculation: 0

Poor neurogenic

First palmar interosseous muscle

L

Normal

Positive sharp waves: 0 Fibrillation: +++ Fasciculation: 0

Poor neurogenic

Legend: 0 (no); + (rare); ++(isolated); +++ (important); ++++ (abundant). L: Left; R: Right.

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Table 5.

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Electroneuromyography of the Lower Limbs (ENMG) Muscle

Side

Insertional Activity

Rest Activity

Recruitment Pattern

Vastus lateralis

R

Normal


Normal

Vastus lateralis

L

Normal


Normal

Vastus intermedius

R

Normal


Normal

Vastus intermedius

L

Normal


Normal

Anterior tibial

R

Normal


Normal

Anterior tibial

L

Normal


Normal

Short extensor muscle of the toes

R

Normal


Neurogenic

Short extensor muscle of the toes

L

Normal


Normal

Legend: 0 (no); + (rare); ++(isolated); +++ (important); ++++ (abundant). L: Left; R: Right.

An electrolyte profile, thyroid function, as well as other viral serologies and basal cortisol levels were normal. The patient had not shown a viral or bacterial infectious prodrome in the preceding days or weeks. No signs of chemical poisoning were evident upon examination. He denied being a drug user. No evidence of functional disease was found. The cerebrospinal fluid (CSF) showed increased protein content, negative cytology and no oligoclonal bands. CSF stains and culture for virus, fungus and bacteria were all negative. Blood and CSF Treponema pallidum Hemagglutination–Venereal-Disease Research Laboratory tests, anti-HU and anti-YO antibodies, Lyme and HTLV-1 serologies, thorax and abdominal CT and MRI of the neuraxis were also non-diagnostic. The patient underwent a bone marrow biopsy to exclude lymphoma. Chronic inflammatory demyelinating polyneuropathy and multifocal neuropathy with conduction blocks were excluded in electrophysiological tests. We made the diagnosis of asymmetric Motor Neuron Disease (MND) associated with axonal acquired neuropathy due to HIV infection. We tried intravenous immunoglobulin (IVIg) treatment aiming to manage the neuropathic clinical aspects, with preliminary results being unsatisfactory. The patient underwent physical and speech therapies for functional problems. He has been on HAART {lamivudine (150 mg), stavudine (30 mg), and nevirapine (200 mg)} for the last 4 years; although not presenting neurological and functional improvements. The patient signed a consent form and was aware of the experimental protocol before participation. The experiment was approved by the Ethics Committee of the Federal Fluminense University.

DISCUSSION The findings observed in neurologic examination and complementary investigation, mainly the NCS and EMG studies, allowed us to conclude that this is a presentation of Motor Neuron (ALS-like) associated with an asymmetric axonal-demyelinating acquired neuropathy. We classified our case as a syndrome of amyotrophic lateral sclerosis (ALS-like), due to the fact that it does not fulfill all the criteria established by EL ESCORIAL [6]. We did not relate the clinical picture of our case to antiretroviral therapy, as the patient started with the symptoms before the HAART. It is known that retroviral infections may cause motor neuron pathology by various mechanisms in animals and humans [4, 6]. Neurological symptoms potentially attributed to damage of lower motor neurons are often described during the course of HIV-1 infection and AIDS. Nevertheless, it is often difficult to establish whether the disorder is primarily affecting the cell body (perikarya) of lower motor neurons. However, could it also be attributed to a focal proximal axonopathy or dying-back process. In summary, our patient has a chronic and progressive disease with clinical and electrophysiological evidence of asymmetric LMN dysfunction in the upper limbs (atrophy, fasciculations, fibrillation potentials, positive sharp waves, neurogenic MUAPs and mild abnormal SNAPs). He has not shown evidence of upper motor neuron dysfunction and does not fulfill all the El Escorial criteria for ALS [6]. As a result, we can only characterize him as having ALS-like or a motor neuron disorder. Such consideration is due to the fact that the diagnosis of ALS would be defined with an evidence of signs of impairment of LMN, through clinical examination,

Motor Neuron Disease and Acquired Axonal Neuropathy Association in HIV Infection

electrophysiological or neuropathological changes, thus associated with clinically proven impairment of the upper motor neuron (UMN) and a chronic and progressive course. There were no signs of involvement of the upper motor neurons in our case. Although there are reports that affirm that a treatment with antiretroviral therapy (ART) stabilizes/improves clinical condition, the weakness and atrophy continued to worsen in our patient even after starting the HAART regimen [9-12]. Reports on HIV-1–associated motor neuron diseases strongly suggest that the association between HIV-1 and ALS is not merely coincidental but etiologically related, and an autopsy-confirmed case has clearly shown loss of motor neurons in the cervical and lumbar horns [7]. An interesting aspect discussed by Casado et al. [13] and presented in our case is the spectrum of ALS-like presentation associated with HIV infection. Although HIVassociated motor neuron disease may be indistinguishable from the classical sporadic ALS, it is often characterized by a variable progressive LMN disorder affecting the limbs or the bulbar muscles; a clinical phenotype similar to sporadic progressive muscular atrophy. Pseudobulbar syndrome is characterized by the association of dysarthria, dysphagia, facial and tongue palsy, brisk gag and jaw reflexes and emotional lability. HIV infection has been occasionally reported to install with pseudo bulbar syndrome, and a causal association between HIV infection and ALS has been discussed previously [13]. Regarding the findings listed above, which are suggestive of bulbar involvement, we found only the presence of mandibular reflex and complaints of dysphonia in our case. Clinically, HIV- related motor neuron disease installs in younger patients and progresses more rapidly than in nonHIV motor neuron disease. The average age of onset is the fourth decade in those with HIV, and the seventh and eighth decades in those without HIV [14]. HAART, specifically stavudine, has been associated with a rare but life-threatening disorder called HIV-associated neuromuscular weakness syndrome (HANWS). It presents with rapidly progressive limb weakness over days to weeks, sometimes including bulbar and respiratory muscles, while being treated with stavudine or within a few weeks after stopping therapy [17]. We reiterate the fact that our patient was not making use of HAART during onset of his clinical symptoms. Systemic illness, thus characterized by nausea, vomiting, abdominal pain, and lactic acidosis, is common in this syndrome. The electrophysiological feature is peripheral nerve axonal injury at most, but sometimes there is an evidence of polyradiculopathy or myopathy. The treatments of weakness varied widely and included IVIg, B1 and B12 vitamins and corticosteroid. In spite of several reports of AIDS-related polyneuropathies as well as of motor neuron diseases caused by antiretroviral drug therapy, our case calls attention to the fact that both entities are present, reflecting a probable viral tropism for both peripheral and central nervous system. Early diagnosis and prompt treatment of these clinical entities should simplify the clinical management of the functional deficiencies presented by the patients and, of

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course, increase the survival span of these patients. Serologic testing for HIV in patients with peripheral nerve disease and/or motor neuron system disease is currently imperative. The role of exercise therapy in ALS-like, myositis and peripheral neuropathy induced to HIV infection has received relatively little attention. Exercises have been shown as a way to improve muscle strength, endurance and well-being. However, there has also been a concern that inappropriate levels of exercise could increase the degree of muscle damage and enhance the inflammatory process. Due to the variability in the degree of weakness, level of endurance, and general level of fitness among HIV patients and associated disorders, as in our case, it is important that any exercise program should be designed for the individual, that the initial exercise load should not be excessive, and that the program could be incremented taking into account not only strength gains but the overall functional capacity of the patient as well. In reference to the nowadays’ notion of evidence-based treatment, there is some evidence supporting the PNF (Proprioceptive Neuromuscular Facilitation) concept as an approach for physical rehabilitation [18-22]. Our patient was subsequently referred to physical as well as speech therapy. A consensus was later reached among the multidisciplinary team regarding prevention of metabolic overload on motor units. We have no preliminary results on this yet. CONCLUSION This and other reports suggest that in some specific settings (especially in monomelic forms, ALS syndrome and some neuropathies), a search for HIV infection is warranted, especially in young individuals. It is important to note that HAART may result in improvement or stabilization of neurologic symptoms. Although there is no evidence that a definitive relationship between HIV infection and ALS exists, the recognition of the simultaneous occurrence of these disorders may play an important role in the eventual discovery of a possible common etiologic mechanism. HIV1 rarely affects neurons, even knowing that, infections may occur predominantly in microglial cells within the central nervous system (CNS) [23]. Primary neurological involvement in HIV infection is presumed to occur by neurotoxic viral protein due to cytokines and chemokines released as a consequence of the HIV disease. The clinical improvement following antiretroviral therapy and the consequent viral suppression, CD4 T-cell elevation and immune reconstitution thus, suggesting an indirect effect of HIV infection in ALS-syndrome. Motor deficit related to the HIV-driven ALS-like syndrome, similar to HIV-associated dementia, can potentially improve with effective HAART [24]. CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest. ACKNOWLEDGEMENTS Declared none.


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PATIENT CONSENT

[12]

Declared none. [13]

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Received: February 2, 2012

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Revised: September 11, 2012

Accepted: September 17, 2012