Tropical ataxic neuropathy – A century old enigma
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.193755
Source of Support: None, Conflict of Interest: None
Tropical ataxic neuropathy, which is prevalent in the tropics causes significant disability as well as increased mortality and remains an enigmatic disease with no effective treatment or cure, even a century after its identification. The syndrome, first described in Jamaica in 1897 and christened as tropical ataxic neuropathy in 1959, is a constellation of bilateral optic atrophy, bilateral sensory neural deafness, predominant posterior column involvement and pyramidal tract myelopathy, with ataxic polyneuropathy. The exact etiopathogenesis remains unresolved, and several factors have been proposed including malnutrition, vitamin B deficiencies, malabsorption, poor protein consumption, chronic cyanide, and nitrile toxicity, with a strong geospatial endemic prevalence in areas of cassava cultivation. In this review, we summarize the history, epidemiology, clinical features, and controversies regarding the pathogenesis and differential diagnosis of the disease and identify the potential areas for further research concerning this debilitating disorder that is common in the tropics. Its multifactorial etiopathogenesis provides potential opportunities for research and international collaboration to identify novel avenues for treatment.
Keywords: Ataxic neuropathy; cassava; cyanide; nitrile; tropical
Neurological syndromes from tropical countries, classified as “tropical myeloneuropathies,” refer to a spectrum of predominantly spastic syndromes that include human T cell lymphotropic virus (HTLV) associated myelopathy, tropical spastic paraparesis, Konzo, and Lathyrism at one end, and the tropical ataxic neuropathies (TAN) at the other. In between this spectrum is the tobacco/nutritional amblyopia, epidemic optic neuropathy and peripheral neuropathy of Cuba, prisoner of war neuropathy (that includes burning feet or happy feet, camp eyes, camp deafness, camp giddiness), and various other opticomyeloneuropathies and polyneuropathies described from Tanzania, West Indies, Senegal, etc., with minor variations. The clinical constellation of bilateral optic atrophy, bilateral sensory neural deafness, predominant posterior column involvement, and pyramidal tract myelopathy, with ataxic polyneuropathy is termed as TAN. Despite the fact that TAN is known for more than a century, an effective treatment for the disease has still not been discovered. In this article, we review its history, current knowledge of epidemiology, clinical features, controversies in pathogenesis, and differential diagnoses, and identify areas where further research is needed.
The major milestones pertaining to TAN, from the time the disease was first described in 1897, are detailed in [Table 1].,,,,,,,,,,,,,,,
Cohorts of more than 3000 participants aged above10 years were followed-up for 2 years in southwest Nigeria (Ososo) where the incidence was found to be 64 per 10000 individuals (male:female = 1:3). A door-to-door census from the same region, screening all participants aged above 10 years, placed the prevalence at 6% (male:female = 1:2). The highest prevalence of 24% was found between the age range of 60-69 years. The prevalence progressively increased with each decade, with a decline after the age of 70 probably due to patients' death.
Interestingly, the disease appears nonexistent in temperate countries barring a single report from Birmingham  of the “prisoners of war neuropathy” occurring in patients who were held captive in tropical countries [Figure 1].
The Indian scenario
TAN remains one of the least reported neurological disorders from India. The first published account was by Krishnaswamy and Kalamangalam in 1975. The next report was from Kerala in 2008. There are no large-scale epidemiological studies of TAN from India that compare the Indian data with the African data. The female preponderance in Indian literature conforms to the African studies. However, the highest prevalence was noted in the third decade unlike in the African population where TAN predominantly affected the elderly population.,
A careful scrutiny of literature reveals the presence of two neurological syndromes that are included in TAN. The first is a syndrome that affects adolescent children, with mucocutaneous manifestations of malnourishment as well as retrobulbar neuropathy, which improves with dietary modification and supplementations of autoclaved dried yeast. Spinal ataxia was noted in half of the patients. The second syndrome affects the middle aged and elderly subjects with varying combinations of sensory polyneuropathy, gait ataxia, optic atrophy, and sensory neural deafness. In contrast to the adolescent syndrome, mucocutaneous manifestations of malnutrition are less frequent (0–30%) and neurological symptoms do not respond to dietary modifications or vitamin supplementation.
The authors analyzed medical records of all patients with TAN investigated with nerve biopsy between January 1999 and July 2015 (unpublished data) at their tertiary care institute, a referral centre catering exclusively to patients with neurological disorders from all over the country. Thirty one cases were evaluated (16 from Karnataka, 10 from Andhra Pradesh, 3 from Tamil Nadu, and 1 each from Kerala and West Bengal). Among these, Kerala is the only state where cassava is grown on a large scale as a staple diet. Seven of the patients were men and 24 were women, aged between 13 and 68 years. Majority were in the age group of 15–25 (n = 13) followed by 26–35 (n = 10), and 36-45 (n = 5) years. Two patients were aged less than 15 years and one patient was 68 years old.
The most common presenting symptom was an abnormal gait followed by sensory symptoms [Table 2]. Eighty-five percent patients had exaggeration of gait difficulty in the dark suggestive of sensory ataxia and half of them had positive washbasin phenomenon. The various sensory symptoms included burning, tingling, pins and needles, a crawling sensation, a tight band around legs, feeling of heat or cold, inability to feel the footwear/ground, feeling of walking on cotton/pebbles, numbness, etc. The Nigerian synonym for the disease originates from the Yoruba word “Ralerale,” which means the reflex of rubbing the soles of feet on the ground to remove phantom soilage. Sensory symptoms in the trunk have been in the form of girdle pains. The sensory symptoms mostly involved the legs. A third-to-half of the patients reported symptoms in the upper limbs with clumsy hands and painful paraesthesias. As noted in other reports, exacerbation of symptoms occur during the rainy season.,, Lower cranial nerve symptoms in the form of dysarthria, dysphagia, and dysphonia occurred in a minority of patients. Dysphonia was manifested (especially common in women) as a high-pitched hypophonic voice with an inability to shout loudly. Dysphonia has not been reported previously. Night blindness was reported in 2 out of 84 patients by Osuntokun, which was attributed to coexistent Vitamin A deficiency. The typical gait was wide based and ataxic that became high steppage if associated with foot drop. The patient's eyes remained glued to the floor. Approximately two-third of the patients reported worsening at night and half gave a history of falls. One-third of the patients reported the use of walking aids.
Evidence of malnourishment included angular stomatitis, chelitis, glossitis, hair loss, discoloration of hair, premature greying of hair, etc., [Table 3]. Cognitive impairment was noted in 2 patients, who developed psychosis with associated visual and auditory hallucinations, and paranoia in tandem with the neurological symptoms. One of these patients had a history of mental retardation from childhood and the other had developed neuropsychiatric syndrome in the postpartum period. A visual acuity of 6/36 or more was categorized as visual impairment, evident in 32 out of 36 patients. Optic atrophy in the form of temporal pallor of the disc or a white contracted disc was often present. Sensorineural hearing loss (present in 24 patients) was evaluated by bedside tuning fork tests. Audiometry was available for 20 patients, of which 19 had confirmed sensorineural deafness. Gaze-evoked nystagmus was seen in 4 patients. Apart from the sensory loss in glove and stocking distribution, hyperesthesia was seen in a minority of patients (n = 2). A sensory level was not seen in any of the patients. Even though incoordination of lower limbs, elicited by the heel knee test was present, other cerebellar tests such as decomposition of movement, intention tremor, rebound phenomenon and adiadochokinesia were absent. Extrapyramidal syndrome of Parkinson's disease, found in a single patient with TAN, was believed to be coincidental. Lack of extrapyramidal involvement is intriguing, considering the fact that cyanide mainly affects the extrapyramidal system, as implicated in the etiopathogenesis. Choreoathetotic movements of lower limbs have been reported in a few patients from the Indian series. However, whether this was extrapyramidal in origin or pseudoathetosis due to loss of proprioception, needs clarification. The presence of primitive reflexes that were not age related probably suggests diffuse cortical involvement and might reflect a degenerative etiology. Two-third of the patients (n = 21) were dependent for mobility and activities of daily living at the time of admission. At discharge, 75% (22/37) felt their symptoms were status quo whereas 8 patients reported mild-to-significant improvement.
Anemia was rare., Hemoglobin, serum albumin, total protein, albumin:globulin ratios, and indices of protein nutrition, have been reported to be normal in TAN. Serum cholesterol level, accepted as an index of calorie consumption, has been found to be lower in patients compared to the control group. The total serum level of vitamin B12 and its metabolism were normal in these patients. Vitamin B nutrition parameters in Nigerian TAN was compared with normal controls on cassava diet and with controls who were not on cassava. The serum riboflavin levels were significantly lower in the patients. Thiamine status, as assessed by transketolase activity of red blood cell hemolysate, was reported to be marginally deficient. Microbiological assays of nicotinic acid, folate, pantothenic acid, and pyridoxine were normal. The serum and urinary thiocyanate levels, indirect measures of cyanide load were significantly elevated , and the sulfur containing aminoacid cysteine, which is the thiol donor for cyanide, that results in the formation of thiocyanate, were reduced. Cerebrospinal fluid (CSF) studies were reported to be normal in most patients , and elevation in protein did not exceed 60 mg/dl, with pleocytosis being mild (in 18 and 15% of patients, respectively). CSF Kahn test for syphilis was consistently negative.
Electrophysiological studies have revealed slowing of motor conductions in the nerves of lower limbs without conduction blocks.,, The sensory conductions revealed complete absence of sural sensory nerve action potentials in all patients. The reduced conduction velocities in the affected nerves suggested a demyelinating disorder. Pathologic or autopsy studies of TAN patients are sparse in the literature. The histopathology of sural nerve biopsy was consistent with predominantly axonal involvement affecting both unmyelinated and myelinated fibres. The latter were most affected without signs of regeneration, suggesting a sensory neuronopathy. Anterior tibial nerve biopsy specimens have revealed perineural infiltration with lymphocytes and perineurial fibrosis in patients with polyneuropathy. The vasa nervorum were usually normal.
In the epidemic Cuban neuropathy, which presented as either retrobulbar neuropathy, sensory peripheral neuropathy, dorsolateral myeloneuropathy, or as a mixed form, the morphological findings in sural nerve biopsies revealed alterations ranging from mild-to-severe axonal damage in all the cases. In a minority of patients, axonal damage was accompanied by perineural fibrosis and vascular abnormalities. Axonal regeneration was noted in 23% and remyelination in 26% patients. Morphometric analysis revealed a predominant loss of myelinated fibers in 92% of the patients that involved large caliber fibers. Scarce mononuclear cells were observed in half of the cases. No virus-like elements were detected. The morphological features in this study indicated that, regardless of the clinical presentation, peripheral nerve lesions of the epidemic neuropathy in Cuba correspond to an axonal neuropathy. These features were compatible with nutritional, toxic, or metabolic etiologies, but were incompatible with an inflammatory etiology. Whether the biopsy findings of epidemic Cuban neuropathy can be extrapolated to TAN is controversial because cassava is not implicated in the etiopathogenesis of Cuban neuropathy.
Whereas these two studies described a predominant axonopathy or sensory neuronopathy in TAN,, other studies provided evidence of a demyelinating neuropathy. Anterior tibial nerve biopsy in the Nigerian tropical ataxic neuropathy revealed sudanophilic granules in the perineurium and endoneurium suggestive of myelin breakdown. There was also reduction in the number of myelin sheaths. Axonal changes were not found to be as striking or extensive as myelin alterations. The blood vessels were congested with moderate proliferation of endothelial cells and occasional ones were showing small areas of infiltration of lymphocytes, plasma cells and mononuclear cells. The perineural connective tissue was thickened by dense fibrous tissue in some nerves and hyalinized collagen in others. Electron microscopy revealed abundant unmyelinated fibres compared to myelinated fibres.
TAN has been associated with malnutrition, vitamin B deficiencies, chronic cyanide intoxication from excessive cassava consumption, tropical malabsorption, a vegetarian diet, a poor protein intake or viral, degenerative, or genetic factors. No single factor has been implicated conclusively.
The interest in cyanide-containing cassava in etiopathogenesis was rekindled in the 1960s. Cassava is described as a food security crop because of its resistance to drought and poor soil. All cassava species contain cyanogenic glycosides in their leaves and roots. The two cyanogenic glycosides are linamarin and lotaustralin (in a ratio of 97:3). During drought conditions, the cassava plant produces more linamarin and bitter cassava has a higher linamarin content than the sweet species. Various processing methods such as fermenting, sun drying, soaking, boiling, roasting, and grinding can reduce the cyanide content by up to 98%. This is achieved by the release of the enzyme linamarinase in the cell wall, which catalyzes the hydrolysis of linamarin to hydrogen cyanide and acetone. The resulting hydrogen cyanide escapes into the atmosphere making the processed cassava edible and safe for consumption. If cassava is inadequately processed, then cyanide reaches the body. Cyanides are highly toxic and inhibit the enzyme cytochrome c oxidase (aa3) in the mitochondria, effectively causing histotoxic hypoxia. The body tries to avoid this by providing hydroxycobalamin and ferric ions from hemoglobin or thiols donated by sulfur containing amino acids, etc., Hydroxycobalamin reacts with cyanide to form cyanocobalamin, which is excreted through urine and bile. Minor amounts get converted to formic acid and are excreted in urine. However, the major pathway of the detoxification of cyanide is its reaction with cysteine to form iminothiozidine compound that is excreted in the saliva and urine. The thiocyanate level in the urine and saliva is considered to be an indirect measure of cyanide load in the body. Hence, effectively, detoxification is dependent on the nutritional status, protein malnutrition, and levels of sulfur containing aminoacids. Experiments to identify the specific etiology for neuropathy caused by cassava have been considered using Wistar strain albino rats as the experimental animal model. The results of cassava-fed animals were compared with control animals, animals given cyanide, malnourished animals, and malnourished animals fed cyanide to identify the causative factors. This study revealed that, although the behavioral pattern in motor coordination of the cassava-fed animals was similar to the other groups studied, the neurochemical basis for the observed behavioral pattern was unique for cassava. Hence, the neurotoxicity of cassava could be attributed to the non-metabolized linamarin, more than its nutritional status and/or cyanide toxicity. Demyelination due to cyanide, high thiocynate levels in serum urine, and nerve specimens of patients, reduction of these levels following diet modification, strong geospatial correlation between endemic areas for TAN and cassava cultivation, all favored cyanide in the etiopathogenesis of TAN.
Although the existence of cyanide as an etiogenetic factor is rather appealing, it is challenged by various other studies that found high thiocyanate levels in Swedish smokers, and in unaffected family members of the patients, a low prevalence in a communities where cassava consumption was very high, and case reports from non-cassava consuming areas. It is interesting that cassava was introduced to Africa from South America sometimes after the 11th century AD, and curiously TAN is not common in South America.
Absence or diminution of sulphur-containing amino acids has also been implicated in the etiology of TAN. The hypothesis that a deficient intake of sulfur-containing essential amino acids due to cassava dominated diet may compromise cyanide metabolism to thiocyanate by rhodanese , needs more research and therapeutic trials.
A novel unifying hypothesis that TAN might be caused by nitriles, which are compounds containing a cyano (R-CN) group, via a neurotoxic action independent of cyanide, in a manner akin to lathyrism, has been suggested recently. There is increasing evidence from limited human and several animal studies that nitriles show a wide variety of neurotoxic properties. Nitriles cause degeneration of vestibular hair cells (loss of balance), auditory hair cells (deafness), corneal clouding, retinal detachment and degeneration (vision loss), and degeneration of olfactory mucosa (anosmia). It also causes neurofilament accumulation with swelling of axons resulting in axonopathy, particularly targeting the larger neurons of dorsal root ganglia and spinal cord motor neurons. The neurotoxic properties of nitriles are determined by their concentration, type of compound structure, the presence of isomeric forms, by their metabolic bioactivation in the body, as well as due to gender and species differences in disease susceptibility.
It has been suggested that certain trace metals such as copper may be of etiological significance because deficiency of copper is known to cause sheep “sway-back.”
The relationship of TAN to parasitic diseases, especially schistosomiasis, has intrigued several researchers in the past.
There have been reports of a possible association between a TAN-like illness with human T lyphotrophic virus (HTLV-2) in 4 female patients with ataxic gait and prominent mental changes. Three of them had motor deficits with urinary frequency and 2 reported nocturnal leg cramps. Only two had antibodies to HTLV 2 in CSF.
Recent studies have re-evaluated thiamine deficiency as the etiological mechanism. The thiamine nutritional status, as assessed by the transketolase activity and thymine pyrophosphate effect, was found to indicate significant thiamine deficiency in patients with TAN. The clinical manifestations of sensory polyneuropathy, optic atrophy, and gait ataxia are compatible with thiamine deficiency. A dramatic and statistically significant improvement in the mean ataxia score of TAN patients as compared to controls occurred in the first week after receiving 100 mg of thiamine.
There might be a complex relationship between the toxicant and the neurological disease, which may be relevant to other toxic or neurodegenerative diseases.
Detoxification of cyanide is carried out by hydroxycobalamin (not cyanocobalamin) and the enzyme rhodanese, both of which are stored in the liver. Sulfur containing amino acids act as thiol donors, which combine with cyanide to form thiocyanate. In a controlled clinical trial, treatment with hydroxycobalamin had no effect. A subsequent placebo-controlled, double-blind clinical trial with cysteine, hydroxycobalamin, and riboflavin administered for 48 weeks also did not find reveal any benefit. Hence, currently, no effective treatment is available.
Prognosis and natural history
There is paucity of information regarding the natural history and age-specific mortality of the disease, even though follow-up studies suggest a higher mortality compared to that seen in the community. In Nigeria, where 84 patients were followed-up for less than a decade, no deaths occurred among the patients, none were paraplegic, and 2 had signs of myelopathy; those who had optic atrophy and deafness at presentation developed a definite polyneuropathy at follow-up that was confirmed by electrophysiological tests. In most patients with deafness, myelopathy and optic atrophy, the symptoms started within weeks of each other. In a few cases, there was a clear history that symptoms of myelopathy preceded the visual impairment and nerve deafness. The spinal nerves were the last to be involved. The longest follow-up study was of ex-prisoners of war from the Far East, who had developed nutritional neuropathy, optic atrophy, sensorineural deafness, etc., and were studied after an interval of 23 to 36 years in Europe. The follow-up of 898 neuropathy patients who were formerly prisoners of war, after a mean period of 32 years after their release and treatment revealed a persistent neurological deficit in 5.5% of them. The residual deficits included peripheral neuropathy, optic atrophy, sensory neural deafness, and myelopathy. In the Indian series, with a median follow-up period of 2 years, sensory ataxia was noted to have improved in 60% patients. However, the improvement was mild in half of the patients and moderate in the other half. The patients who had initially been chair-bound, were able to walk unaided within 1 year. None showed improvement in the visual and hearing deficits and there were no fatalities. The ataxic neuropathy with nutritional mucocutaneous manifestations, especially in adolescents and young adults improved with diet and nutritional supplementation whereas neurological symptoms due to Tan in the elderly patients that were attributed to cassava did not show improvement.
A combination of ataxia (sensory and cerebellar) along with pyramidal signs may be seen in high cervical cord lesions, craniovertebral junction (CVJ) anomalies or vascular malformations of the area. A combination of deafness or optic atrophy may be seen in a small percentage of patients with syrinx and CVJ anomaly. In the presence of peripheral neuropathy, the syndrome becomes a myeloneuropathy, and the possibility of a structural lesion gets excluded. The etiology of myeloneuropathies could be nutritional, toxic, paraneoplastic, autoimmune, metabolic, or infectious, as enumerated in [Table 4]. A detailed history covering dietary habits including cassava consumption, symptoms related to malabsorption, systemic symptoms related to autoimmune or infectious diseases, epidemiologic or genetic factors, recent illnesses, surgeries, toxin exposure, and drug intake needs to be obtained. An MRI of the spine should be performed to detect any structural pathology. Laboratory evaluation should include nutritional indices, peripheral blood smear, various vitamin levels, homocysteine, methylmalonic acid and copper levels, autoantibody, onconeural antibody and paraprotein titers. Screening for various infections, genetic studies, liver, minor salivary glands or nerve biopsies tailored to the patients clinical picture, should also be performed.
“Whatever the agents responsible for these myeloneuropathies turn out to be, the history of lathyrism warns us that the exact role of a suspected food stuff may long elude us.” Lathyrism is one of the oldest neurotoxic diseases known to mankind. Hippocrates (460 to 377 BC) is believed to have been aware of the toxic pea causing persistent paralysis of the legs. It remained a mystery for centuries until two groups of Indian scientists in 1964 identified beta-N-oxalyl amino-L-alanine after primate feeding studies. If cassava consumption is indeed responsible for cases of TAN, there are significant public health implications. It is the poorest populations of subsistence farmers who are most dependent on cassava for food and nutritional security, and would therefore be at most risk for developing the neurological effects of TAN. In areas with high consumption, proper processing of cassava may need to be emphasized, as improper processing yields highly toxic food products. For detoxification of cyanide, sulphur-containing amino acids are necessary that are often lacking in tropical diets, which may be countered with measures to combat protein malnutrition.
Cassava can be grown in relatively hostile environments and has a high caloric content. As such, any food that may be promoted instead of cassava would have to adequately substitute these important qualities.
TAN being a serious and disabling health problem and multifactorial in etiopathogenesis, provides unsurpassed opportunities for research and international cooperation to identify new avenues for treatment and to unravel the pathogenesis of this mysterious toxic-metabolic neuropathy. It is rather astonishing how little literature has come from India where the disease is not at all uncommon!
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]