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The Expanding Spectrum of Human T-cell Lymphotrophic Virus 1-Associated Neurological Disease: A Case Report and Review of the Literature

Guzman, Nilmarie MD; Sands, Michael MD, MPH, TM, FIDSA

Infectious Diseases in Clinical Practice: July 2007 - Volume 15 - Issue 4 - p 236-238
doi: 10.1097/IPC.0b013e3180686d32
Review Article

Human T-cell lymphotrophic virus 1 is classically associated with tropical spastic paraparesis. A recent case and review of the literature reveal an expanding spectrum of human T-cell lymphotrophic virus 1-associated neurological diseases.

Division of Infectious Diseases, Department of Medicine, University of Florida-Jacksonville, Jacksonville, FL.

Address correspondence and reprint requests to Nilmarie Guzman, MD, Division of Infectious Diseases, Department of Medicine, University of Florida-Jacksonville, 1833 Blvd, Suite 500, Jacksonville, FL 32250. E-mail:

Human T-cell lymphotrophic virus (HTLV) 1 is a human retrovirus that belongs to the genus Deltaretrovirus. Infection with HTLV-1 is recognized as a global epidemic affecting approximately 10 to 20 million people worldwide with a high prevalence detected in Japan, the Caribbean region, Central and South America, Central Africa, and the Melanesian islands. Although HTLV-1 infection is asymptomatic in most infected patients, it can produce a variety of illnesses in 1% to 5%, which may include adult T-cell leukemia/lymphoma, Strongyloides stercolaris hyperinfection, crusted scabies, uveitis, and tropical spastic paraparesis (TSP) or HTLV-1-associated myelopathy (HAM).1

Tropical spastic paraparesis is the neurological syndrome most commonly associated with HTLV-1 infection. The features of this syndrome comprise the gradual onset of lower extremity spastic paraparesis with bladder and/or bowel dysfunction. However, an increasing number of reports suggest that the spectrum of neurological diseases associated with HTLV-1 is diverse, not only limited to the classically recognized lower extremity disease.2-4

We report a case of HAM/TSP in a woman without a history of travel or residence in an endemic area and with atypical neurological features to emphasize the expanding spectrum of HTLV-1-associated neurological diseases and the need to recognize and include HTLV-1 infection in the differential diagnosis of a wide variety of neurological syndromes.

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A 52-year-old African woman from Florida was admitted to the university hospital, complaining of bilateral lower extremity weakness associated with rigidity and an unsteady gait. Her symptoms had been progressively worsening during the previous 8 months. The patient also complained of upper and lower extremity paresthesia and urinary incontinence.

She denied fever, chills, seizure disorder, or history of brain or spinal cord trauma. Her medical history was relevant for hypertension and a remote history of treated early syphilis. She was being treated with amlodopine and benazepril for her hypertension, tolterodine for bladder dysfunction, and cyclobenzaprine for spasticity.

The patient denied cigarette smoking, ethanol abuse, or illicit drug use. She had no history of international travel. She had been sexually active in the past year with a single new partner of Caribbean descent. Other than 2 cesarean deliveries, the patient had no other surgical procedures.

On physical examination, her blood pressure was 119/71, heart rate was 91 beats per minute, temperature was 97.9°F, and respiratory rate was 18 breaths per minute. General findings on physical examination were unremarkable. On neurological examination, she was alert and oriented in all spheres. Cranial nerves were intact including normal tongue motility and positioning and normal speech pattern. Neck flexion and extension were completely normal and without rigidity. Her muscle strength was graded as follows (right/left): in the arms and hands-deltoids, 5/5; biceps, 4+/5; triceps, 5−/5; wrist extension, 5−/4+; abductor pollicis brevis, 4+/4; ulnar intrinsic hand muscles, 5/5; in the legs-iliopsoas, 4+; quadriceps, 5−/5; hamstrings, 4+/4; tibialis anterior, 5−/4+; gastrocnemius, 5. Reflexes were 3 in the upper extremities and 4 at the ankles, with 3 to 4 beats of clonus bilaterally and with up-going plantar responses.

Baseline laboratory tests showed a white blood cell count of 4.7 × 103/mm, hemoglobin level of 13.8 gm/dL, and hematocrit of 40.5%. Cerebrospinal fluid analysis showed 13/cmm white blood cells with 90% lymphocytes, protein of 46 mg/dL, glucose of 86 mg/dL, and negative bacterial, fungal, and mycobacterial culures. Cerebrospinal fluid CMV-DNA was negative. A serum protein electrophoresis showed diffuse hypergammaglobulinemia. Erythrocyte sedimentation rate was 26 (reference range, 0-30), and C-reactive protein was 8 mg/L (reference range, 0-4.9 mg/L). Serum human immunodeficiency virus test by enzyme-linked immunosorbent assay was negative, and HTLV-1 Ab by enzyme-linked immunosorbent assay was positive.

Magnetic resonance imaging with and without contrast of the brain and cervical, thoracic, and lumbar spine were all interpreted as normal. An electromyogram study of the arms and legs showed abnormal spontaneous activity in all 4 extremities that varied from mild to moderate in both proximal and distal muscles. A mild degree of abnormal spontaneous activity was also detected in the rectus abdominis muscles. The neurology consultant felt that the patient had a combination of upper and lower motor neuron dysfunction related to HTLV-1 infection and made the diagnosis of TSP/HAM. She was discharged from the hospital receiving baclofen, temazepan, and tolterodine with neurology follow-up.

One year after discharge, the patient continues to have significant upper and lower extremity muscle weakness with hyperreflexia and a wide-based ataxic gait. She also developed a neuropathic bladder requiring to catheterize 2 to 3 times a day. The patient continues to complain of stiffness in both lower extremities associated with pain at the level of both ankles and persistent paresthesias described as a sensation of walking over sandpaper.

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Human T-cell lymphotrophic virus 1 is recognized as the etiologic agent for TSP, also termed HTLV-1-associated myelopathy or HAM. The classically described presentation of TSP from endemic areas involves gait disturbance, followed by gradually increasing spasticity and lower extremity weakness, back pain, urinary incontinence, and impotence in men.1 However, recent reports suggest that patients with HTLV-1 infection may develop a wide spectrum of neurological complications (Table 1).2-6 Human T-cell lymphotrophic virus 1 infection may also present with accelerated neurological disease progression.7



Our patient presented with a significant degree of neurological deficit associated with HTLV-1 infection. Her symptoms and physical findings correlated with a complex clinical picture that did not precisely fit the criteria for diagnosis of TSP/HAM. She had advanced quadriparesis, incapacitating lower extremity weakness, and significant upper and lower extremity spasticity. The findings of her neurological examination correlated with a markedly abnormal electromyogram study, suggesting significant anterior horn cell involvement.

As noted, patients with TSP/HAM usually present with lower extremity symptoms; however, our patient additionally had a significant degree of upper extremity involvement, manifested by weakness and spasticity. Upper extremity involvement has been described in patients with HAM/TSP but is not a common clinical feature described in the most recent literature. Gotuzzo et al7 published a series of 165 patients with HAM/TSP from Peru, describing their most common characteristics at presentation, which included spasticity, hyperreflexia, lower limb paresthesia, pyramidal signs, urinary complaints, and lumbar pain. Upper extremity involvement or quadriparesis was not a noted feature in that series. Jean-Baptiste et al,8 in 1987, described the main clinical features in 25 patients from an HTLV-1 endemic region, which did include upper limb involvement with bladder dysfunction. In a series of patients with atypical neurological manifestations associated with HTLV-1 infection, Carod-Artal et al9 conclude that the presence of a cerrebellar syndrome or neuropathy of uncertain etiology in endemic areas should lead to the inclusion of HTLV-1 infection in the differential diagnosis, even in the absence of TSP.

Another uncommon feature of the HTLV-1 neurological illness in our patient was the relative rapidity of disease progression. Her symptoms progressively worsened from lower extremity weakness to quadriparesis in an 8-month period. Published data on rapid disease progression of HTLV-1 infection are very scarce. The study done by Gotuzzo et al7 found that 22% of their patients experienced rapid disease progression, taking into consideration lower extremity symptoms only. Rapid progression of neurological symptoms caused by HTLV-1 infection has been linked to several risk factors, such as high age at onset, parenteral HTLV-1 transmission, high provirus loads, and high antibody titers.10-14

Given the appreciation of the potential broad spectrum of neurological disorders associated with HTLV-1 infection, this type of infection should be included in the differential diagnosis of patients presenting with a wide variety of undiagnosed neurological diseases involving the spinal cord and peripheral nervous system, particularly in patients from countries of HTLV-1 endemicity or having sexual or parenteral exposure to populations or blood products from endemic areas.

There is currently no criterion standard single test for the diagnosis of HTLV-1-associated disease. In 1989, a panel of scientists convened by the World Health Organization15 developed a series of diagnostic guidelines for the diagnosis of TSP/HAM. The proposed guidelines involved the correlation of neurological symptoms with laboratory testing. The presence of HTLV-1 antibodies or antigens in blood and cerebrospinal fluid, associated with neurological deficit, is highly suggestive of the diagnosis.

However, several other laboratory findings have been identified in patients with HTLV-1 infection and, although nonspecific, may be suggestive of HTLV-1-associated neurological disease in the absence of another etiologic diagnosis (Table 2).16 Recent literature emphasize the diagnosis of HTLV-1 infection by detecting viral particles by polymerase chain reaction methodology; in fact, some clinicians have correlated advanced disease progression with high plasma viral loads.



Radiological findings reported in patients with TSP/HAM, usually involve cerebral white matter lesions and spinal cord abnormalities, such as edema.

Unfortunately, treatment options for patients with neurological complications of HTLV-1 infection are very limited. A limited number of patients with TSP/HAM have benefited from corticosteroid therapy, cyclophosphamide, and interferon alfa, particularly when given early to patients with rapid disease progression. Adjunctive therapies have been used with different outcomes to patients with multiple clinical manifestations. Danazol is frequently used for the management of urinary and fecal incontinence but has no effect against spastic limb disease. Bladder symptoms have been managed with tolterodine, and spasticity can be treated with muscle relaxants.

In 1996, Nakagawa et al17 published the results of therapeutic trials in 200 patients with TSP/HAM. He observed that motor disability was improved by several treatment modalities including immunosuppressive therapy, plasmapheresis, antibiotics, and thyrotropin-releasing hormone, with the highest response rate achieved with oral administration of prednisolone (69.5%).

Painful dysesthesias have been treated with antidepressants, anticonvulsants, or opioids. These treatment approaches are not always effective in patients with dysesthesias, and therefore, other strategies have been recently explored. Kubota and Miyata18 published a case report on an advanced case of TSP/HAM refractory to amitriptyline, zonisamide, and oxycodone that was successfully treated with ketamine for pain control.

Plasma exchange is another proposed strategy to improve disability in some patients, but studies using this approach have involved only a small number of patients.1,17

With the molecular similarities between HTLV-1 and human immunodeficiency virus, it has been hypothesized that HTLV-1 infection treatment should include reverse transcriptase inhibitors. Research data on this are very scarce, with some clinical trials involving a small number of patients. At the present time, there are no standardized recommendations for antiretroviral therapy in the management of HTLV-1 infection.

We conclude that infection with HTLV-1 can lead to a wide variety of neurological disorders, not limited to the manifestations classically associated with TSP/HAM. These include a spastic quadriplegia, cervical myelopathy, spinocerebellar syndrome, unexplained peripheral neuropathy, and cognitive dysfunction. The tempo of neurological morbidity is also quite diverse, with a minority of patients experiencing rapid disease progression.

We recommend that HTLV-1 infection should be included in the differential diagnosis of patients presenting with a wide variety of undiagnosed neurological diseases involving the spinal cord and peripheral nervous system, particularly in patients from countries of HTLV-1 endemicity or having sexual or parenteral exposure to populations or blood products from endemic areas.

Further research is needed to understand the pathogenesis of HTLV-1 infection in patients with advanced disease progression and on possible future treatment options.

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