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). However, TAN and HAM/TSP have 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
Tropical ataxic neuropathy (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. However, no actual causal relation between cassave and TAN has been established. [1] 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. Despite all these theories, the actual etiology remains unknown. [1]
HTLV-1–associated myelopathy/tropical spastic paraparesis (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. [2] 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. [3]
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. [4]
Epidemiology
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. [5]
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.
TSP has been reported in India as well and one case series identified 25 patients. Only one patient was found to be positive for HTLV-1.{ref53]
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
Studies on mortality and morbidity of TAN are very scarce; however, one study conducted in Nigeria showed high mortality in TAN population compared to the rest of the community. Interestingly, the mortality was not related to greater exposure to cyanide from cassava foods. [6]
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.
Age of onset at 50 years or older and high HTLV-1 proviral load are associated with a more rapid progression to a severe disability. [7]
Patients may survive for 10-40 years. Those who die early are paraplegics, who develop repeated urinary infection or pulmonary emboli.
Demographics
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.
TAN and HAM/TSP generally affect women more than men, with a female-to-male ratio of 3:1. One small case series of 25 patients from India found more male predominance with a ratio of 2:1. [8]
TAN and HAM/TSP may occur at any age, with a peak in the third or fourth decade.
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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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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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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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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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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.)
