AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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Background

Tropical myeloneuropathies were described initially in tropical countries and are classified into 2 clinical syndromes that can have overlapping features—tropical ataxic neuropathy (TAN) and tropical spastic paraparesis (TSP). TAN and TSP are 2 separate diseases that are grouped together because they both occur predominantly in tropical countries. TSP also has been described in temperate countries (eg, southern Japan) as HTLV-1–associated myelopathy (HAM). TAN and HAM/TSP have, however, different etiologies and clinical presentations. TAN is predominantly a sensory neuropathy, whereas HAM/TSP affects predominantly the spinal cord, resulting in an upper motor neuron syndrome.

Pathophysiology

TAN is predominantly a sensory neuropathy. This disorder is encountered frequently in malnourished populations. TAN is observed quite frequently in populations that use large quantities of cassava in their diets. The bitter varieties of cassava have a relatively high content of cyanide. However, the exact mechanism of cyanide neurotoxicity is unknown. Cassava is resistant to drought, but levels of cyanogenic glycoside increase in the dry season, even in sweet varieties. Preparation of cassava by using soaking and grating methods removes 90% of glycoside content, thereby reducing the incidence of TAN. B-group vitamin deficiency was thought to produce this disorder, but treatment trials with such vitamins were not successful. In prisoners of war during World War II and the Korean War, TAN was thought to be caused by vitamin deficiencies and/or tropical malabsorption. In most cases, the affected individuals were deficient in group B vitamins.

HAM/TSP is an upper motor neuron syndrome affecting primarily the lower extremities. While seronegative TSP has been described, by definition patients with HAM are infected with HTLV-1. HTLV-1 is a type C retrovirus, related to other human and primate lymphotropic viruses and the bovine leukemia virus. Several studies indicate that HTLV-1 transmission occurs through sexual or other intimate contact—intrauterine, perinatal, breastfeeding, sharing of needles by drug users, or blood transfusion from infected persons. One study showed that transfusion of HTLV-1 antibody-positive blood causes seroconversion in 60% of recipients. Transfusion of plasma alone in humans did not result in seroconversion.

The pathogenesis of HAM/TSP is still a matter of debate in the literature. Whereas only a small proportion of HTLV-1–infected individuals develop HAM/TSP (1-4%), the mechanisms responsible for the progression of a HTLV-1 carrier state to clinical disease are not clear. No specific sequence differences have been found between HTLV-1 recovered from patients with HAM, those with adult T-cell leukemia/lymphoma also caused by HTLV-1 (ATLL), and HTLV-1 carriers. According to one theory, supply of HTLV-1–infected CD4 cells via the blood to the CNS is essential for development of CNS lesions. Both anatomically determined hemodynamic conditions and adhesion molecule-mediated interactions might contribute to localization of the lesions. Several studies have found a correlation between a high proviral load in CSF and peripheral blood and symptom severity in HAM/TSP. Another small study found an association of vitamin D receptor gene ApaI polymorphism with susceptibility to HAM/TSP.

Following stimulation by HTLV-1 antigens on the surface of infected T cells in the CNS compartment, expansion of immunocompetent T cells directed against viral proteins may result in CNS tissue damage, which may be mediated by cytokines such as tumor necrosis factor (TNF) alpha.

Frequency

United States

HAM/TSP: Sporadic cases have been reported in the United States, mostly in immigrants from countries where this disease is endemic. In the United States, the lifetime risk of an HTLV-1–infected person developing TSP/HAM has been calculated to be 1.7-7%, similar to that reported for United Kingdom, Africa, and the Caribbean.

International

TAN and HAM/TSP: The incidence is difficult to estimate because of the insidious nature of these diseases.

TAN: The prevalence in some areas in Africa ranges from 29-34 cases per 1000 inhabitants. In 1981 during a drought, several epidemic outbreaks of cassava-related TAN were described. A particularly severe outbreak, called "mantakassa," took place in Mozambique. More than a thousand cases of spastic paraparesis were reported, affecting women and children in particular.

HAM/TSP is common in regions of endemic HTLV-1, such as the Caribbean, equatorial Africa, Seychelles, southern Japan, and South America. However, it also has been reported from non-endemic areas, such as Europe and the United States. The prevalence in southern Japan is in the range of 8.6-128 cases per 100,000 inhabitants. An estimated 10-20 million individuals worldwide are carriers of HTLV-1.

Interestingly, the lifetime risk of an HTLV-1–infected person from Japan developing HAM/TSP has been calculated at 0.25%, which is much lower than in other countries.

Mortality/Morbidity

HAM/TSP: The incubation period from infection to onset of myelopathic symptoms is believed to range from months to decades. This period is usually shorter in cases in which HTLV-1 was acquired by blood transfusion.

Patients may survive for 10-40 years. Those who die early are paraplegics, who develop repeated urinary infection or pulmonary emboli.

Race

• TAN is prevalent in Africa and tends to affect people from lower socioeconomic classes.
• In Africa and the Caribbean, most patients with HAM/TSP are from the lower socioeconomic class and usually of black or mixed origin.

Sex

TAN and HAM/TSP generally affect women more than men, with a female-to-male ratio of 3:1.

Age

TAN and HAM/TSP may occur at any age, with a peak in the third or fourth decade.

CLINICAL

Section 3 of 11  

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History

• TAN
• • Difficulty walking
  • Burning pain in the hands and feet
  • Amblyopia (in some prisoner-of-war camps, as many as two thirds lost vision)
  • Subacute or chronic onset
• HAM/TSP
• • Presenting neurological symptoms in 80% of cases - Gradual onset of leg weakness, back pain, paresthesias, and impairment of urinary or bowel function
  • Erectile dysfunction possible - In one case report, the presenting symptom
  • Increased urinary frequency
  • Dermatitis or psoriasis

Physical

• TAN
• • Impaired light touch and vibration sensation and proprioception
  • Gait ataxia
  • Romberg sign
  • Hyporeflexia or areflexia
  • Sensorineural hearing loss
  • Muscle weakness and atrophy that can involve upper extremities
  • Similar symptoms were described among prisoners of war in the tropical and subtropical regions.
• HAM/TSP
• • Spastic paraparesis or paraplegia with hyperreflexia, clonus, and extensor plantar responses; weakness of the lower extremities, more marked proximally
  • Decreased touch and pinprick sensation in poorly defined thoracic areas
  • Vibration sensation frequently impaired, especially in the lower extremities, resulting from spinal cord or peripheral nerve involvement
  • Low lumbar pain with radiation to the legs
  • Hyperreflexia of upper extremities frequently associated with Hoffmann sign
  • Less frequent neurological findings - Cerebellar signs (ie, intentional tremor, dysmetria), optic nerve atrophy, deafness, nystagmus, cranial nerve deficits, upper extremities tremor, absent or diminished ankle jerk
  • Increased urinary frequency - Due to detrusor hyperreflexia (ie, neurogenic bladder) associated with increased incidence of urinary tract infection

Causes

• TAN
• • In many cases, TAN is associated with excessive consumption of cassava, also known as the mandioca or tapioca plant, which is one of the most important sources of calories in the tropical countries. About 300 million people depend on it for subsistence, especially in the tropical regions of the Americas and in Africa. Cassava contains cyanide in the form of a cyanogenic glycoside, linamarin, which releases cyanide by the enzymatic action of linamarinase or by hydrolysis. Chronic cyanide intoxication has been confirmed as the cause of the TAN described in Nigeria and Tanzania. In these patients, treatment with high-dose vitamins was not satisfactory, suggesting that the vitamin deficiencies are not important in the etiology of the disease in these cases.
  • Processing of the cassava flour removes almost all the cyanide, but during a drought, these procedures tend to be shortened or ignored. Many people, especially women and children, eat the cassava raw or merely sun dried. The cyanide content of cassava increases during a drought, which may lead to a relatively higher incidence of severe cyanide intoxication.
  • Vitamin deficiencies and tropical malabsorption were the causes of TAN in prisoners of war. In most of the cases, the affected individuals were deficient in group B vitamins.
• HAM/TSP
• • TSP is caused by an infection with HTLV-1.
  • Cases of TSP have been documented in which HTLV-1 was not detected.

DIFFERENTIALS

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Other Problems to be Considered

Lathyrism
Hereditary spastic paraparesis
Compressive myelopathy

WORKUP

Section 5 of 11  

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Imaging Studies

• HAM/TSP
• • Radiographs of the chest and myelogram are normal.
  • MRI of the spinal cord is indicated to rule out other causes of myelopathy and may show evidence of demyelination. Similar changes can occur in the periventricular white matter. Cord swelling or atrophy has been noted in a few cases.

Other Tests

• TAN
• • Nerve conduction studies and electromyography (NCS/EMG) typically show reduction in sensory conduction velocities.
  • Motor nerve conduction study findings are usually normal.
• HAM/TSP
• • Electrophysiological abnormalities often are noted below the cervical spinal cord. The most common somatosensory evoked potential study (SEP) finding is abnormal central conduction time in the lower extremity. Electric brain stimulation (caution: not approved by the US Food and Drug Administration [FDA]) often reveals abnormal motor evoked potentials. Visual and auditory evoked potentials are occasionally abnormal.
  • NCS/EMG usually reveals slow conduction velocity and prolonged distal latency. These findings are suggestive of a demyelinating polyneuropathy. Needle EMG often shows increased insertional activity (fibrillations and positive sharp waves) in lower thoracic paraspinal muscles.
  • Between 25% and 60% of patients have a mild lymphocytic pleocytosis ( <50 cells/µL) in the cerebrospinal fluid (CSF). A higher percentage have mild protein elevation. Most patients have CSF oligoclonal bands.
  • Patients have high titers of HTLV-1 antibodies in serum and CSF. Enzyme-linked immunosorbent assay (ELISA) or the particle agglutination method is used to detect antibodies to core, envelope, and tax viral proteins. Western blot assay can confirm the diagnosis and distinguish HTLV-1 from HTLV-2. Polymerase chain reaction (PCR) for tax and pol also can be used on peripheral blood cells and CSF cells from infected individuals. PCR is able to distinguish HTLV-1 from HTLV-2. The HTLV-1 proviral load in peripheral blood mononuclear cells is 10- to 100-fold higher than that in CSF. Patients with high proviral load and no intrathecal synthesis antibodies to HTLV-1 have more rapid progression to serious clinical disease.
  • Urodynamic examinations reveal mainly a detrusor external sphincter dyssynergia.
  • Sural nerve biopsy can reveal inflammatory infiltrates, axonal degeneration, and segmental demyelination.

Histologic Findings

• TAN
  • Autopsies in a group of ex-prisoners of war revealed posterior column demyelination, particularly of the fasciculus gracilis and the optic nerves (primarily the papillomacular fibers).
  • Nerve biopsies in a group of Nigerian patients showed nonspecific patchy demyelination with variable pericapillary cellular reaction and perineural fibrosis.
• HAM/TSP (see Images 1-5)
  • A histopathological study of 15 Jamaican patients revealed chronic inflammation with mononuclear cell infiltration of the meninges and the gray and white matter along with proliferation of the small parenchymal vessels and perivascular cuffing (primarily lymphocytes). Demyelination was most marked in the lateral columns but also was seen in nerve roots. In the areas of most severe demyelination, the axons were relatively well preserved. The gray matter was affected to a lesser degree, although changes were sometimes observed in anterior cells. The spinothalamic and spinocerebellar tracts usually showed less severe demyelination, but when damage was severe, focal spongiosis was seen.
  • A detailed Japanese study of 7 autopsies revealed the same pattern of inflammation. Immunohistochemistry demonstrated T-cell dominance. The numbers of CD4 and CD8 cells were equal in patients with shorter clinical courses. CD8 cells predominated over CD4 cells in patients with prolonged clinical courses. In situ PCR demonstrated HTLV-1–infected cells exclusively in the perivascular mononuclear infiltrates.

TREATMENT

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Medical Care

The mainstay of treatment is symptomatic. No standard treatment is available for TAN or HAM/TSP.

• HAM/TSP: A study of 131 patients reported that oral methylprednisolone produced excellent to moderate responses in 69.5% of patients (Nakagawa, 1996).
• • Symptomatic treatment is similar to that used in primary lateral sclerosis (please see article Primary Lateral Sclerosis for further details). Drugs that can be used include baclofen, tizanidine, and benzodiazepines. Physical therapy is used commonly in combination.
  • Patients with HAM/TSP or TAN sometimes report neuropathic pain. Useful drugs include antiepileptics (eg, carbamazepine, phenytoin, gabapentin, topiramate), baclofen, and tricyclic antidepressants. The dosages used usually are well bellow those used in the treatment of epilepsy. None of these drugs are approved by the FDA for this purpose.
  • Controlled trials of antiviral agents (eg, zidovudine) in HAM/TSP are under review.

Consultations

Infectious disease specialist

Diet

TAN: Supplementation with multivitamins is recommended, but in most cases only minor improvement occurs. In areas where cassava flour is used, following standard cassava processing measures is imperative.

MEDICATION

Section 7 of 11  

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HAM/TSP

A multicenter, randomized, double-blind study in 48 patients indicated that treatment with subcutaneous interferon alfa (Roferon) 3 million U (MU) twice a week was effective in more than 66.7% (Izumo, 1996). In another study, 32 patients were treated with interferon alfa; 20 patients showed a fair-to-excellent response in motor function. The effect was sustained, however, for only 1-3 months after the last injection (Nakagawa, 1996).

An open-label study showed that pentoxifylline 300 mg PO once a day induced clinical improvement in 14 of 15 patients. The authors postulated that the effect probably was due to TNF-alpha suppression (Shirabe, 1997). In a recent open-label trial, 12 patients with HAM/TSP were treated with doses of interferon beta-1a of up to 60 µg twice weekly. During the trial, the therapy reduced the HTLV-1 tax messenger RNA load, but the HTLV-1 proviral DNA load remained unchanged. Some measures of motor function were improved, and no significant clinical progression occurred during therapy (Oh, 2005).

Drug Category: Interferons

These agents are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions.

Drug Category: Blood viscosity reducer agents

These agents decrease the viscosity of blood.

FOLLOW-UP

Section 8 of 11  

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Further Outpatient Care

• Physical therapy with strengthening exercises may be of benefit.
• Occupational therapy is indicated for upper limb functioning and can provide assistive devices.

Deterrence/Prevention

• An important component in care of patients with TSP is prevention of infection with HTLV-1 virus. Several studies indicate that transmission of the HTLV-1 virus occurs through sexual or other intimate contact -- intrauterine, neonatal contact, perinatal exposure via breast milk, sharing of needles by drug abusers, and blood transfusion from infected persons. One study showed that transfusion of HTLV-1 antibody-positive blood causes seroconversion in 60% of recipients. Transfusion of plasma alone in humans did not result in seroconversion. Breastfeeding is contraindicated for mothers who are carriers of HTLV-1.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• TSP/HAM can be misdiagnosed as spinal multiple sclerosis (MS). HTLV-1 serum antibodies screen may be indicated in the initial workup of MS, especially when risk factors are present and symptoms are predominantly spinal.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Light microscopy of thoracic spinal cord of 2 patients with HTLV-1–associated myelopathy (Klüver-Barrera staining). (Source: Aye et al, 2000, Fig. 1.)
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Media type:  Photo

Media file 2:  Light microscopy of perivascular inflammatory infiltration in the spinal cord (A, C) and in the brain (B, D) (A, B H&E; C, D Elastica Van Gieson; A, C x400; B, D x200). (Source: Aye et al, 2000, Fig. 2.)
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Media file 3:  Light microscopy of the middle thoracic spinal cord (A, C, E) and subcortical white matter of the brain (B, D, F). Fibrotic changes are seen even in the capillaries (arrows) (A, B, F H&E; C-E Elastica van Gieson; A, C, D, F x400; B x300; E x100). (Source: Aye et al, 2000, Fig. 3.)
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Media type:  Photo

Media file 4:  Immunostaining of the infiltrating cells in the thoracic spinal cord (A, C, E) and subcortical white matter of the brain (B, D, F) (A, B UCHL-1 [antibody to CD45RO]; C, D CD8; E, F OPD-4; A-F x150). (Source: Aye et al, 2000, Fig. 4.)
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Media type:  Photo

Media file 5:  Immunostaining of the infiltrating cells in the thoracic spinal cord (A, C) and subcortical white matter of brain (B, D) (A, B UCHL-1[antibody to CD45RO]; C, D CD8; A-D x160). (Source: Aye et al, 2000, Fig. 5.)
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
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• References

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Article Last Updated: Jan 11, 2007