Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 102

Tropical myelopathies GUSTAVO C. ROMA´N* Department of Neurology, Weill Cornell Medical College, Methodist Neurological Institute, Houston, TX, USA

INTRODUCTION The term tropical myelopathies addresses the multiple disorders of the spinal cord occurring in the tropics, i.e., the parts of the world situated between 23 270 latitude north and south of the Equator between the tropics of Cancer and Capricorn. This geographic definition includes most of Africa, Latin America, Asia, and Oceania. In addition to warm temperatures, days and nights of equal length, and abundant sunlight exposure, other environmental factors play a major role in determining the pattern of neurologic pathologies affecting the inhabitants of the tropics. According to Poser and Poser (2006), in tropical regions: highly influential environmental factors include extreme poverty, famine and malnutrition; lack of medical care and/or access to it; inadequacy or total lack of public health organization; war and political instability together with the population dislocations that ensue; gender and ethnic—cultural discrimination and infringement of civil rights, racial and religious persecution; climatic catastrophes such as tsunamis, earthquakes or typhoons; as well as tribal, cultural and family traditions. Many of these problems derive from what may well be the single-most important adverse environmental factor, overpopulation. It is a combination of these factors along with genetic profiles more than warmth and humidity that define tropical or developing countries. Many of what we now call tropical diseases were, at one time, widespread: leprosy, malaria, cholera and plague were well known in Western countries and temperate climates. In summary, the principal determinants of neurologic diseases in underdeveloped countries are lack of

education and poor socioeconomic conditions (Toro et al., 1983; Roma´n, 2005; Poser and Poser, 2006). The multiple causes of spinal cord injury in the tropics include etiologies also seen in temperate regions (Table 102.1). The recent introduction of brain and spinal cord imaging, in particular computed tomography (CT) and magnetic resonance imaging (MRI), in tropical countries has allowed a better definition of the magnitude of these pathologies. For instance, in Tanzania, Zellner et al. (2010) compared rural and urban spinal pathologies on CT/MRI of the spine demonstrating the preponderance of infectious extradural-extramedullary pathologies (tuberculosis and brucellosis) in the rural areas presenting with lumbar pain; in comparison, common pathologies were observed in the city of Dar es Salaam, including herniated discs and disc protrusions (81%) followed by spinal canal stenosis (7%), fractures of vertebrae (4.4%), and a lesser number of infections – in particular tuberculosis (Pott’s disease), as well as inflammatory lesions such as ankylosing spondylitis, and metastatic cancer. Overall, intradural-extramedullary lesions were rare (meningioma, neurofibroma). Intramedullary pathologies included syringomyelia, congenital anomalies, vascular malformation, myelitis, chronic myelopathy, and demyelinating diseases including multiple sclerosis (MS), granulomatous lesions (tuberculosis, sarcoidosis), ependymoma, astrocytoma, metastases, and spinal cord trauma. In large areas of the tropical world, including Africa and the Middle East, the Caribbean, Venezuela and Brazil, bilharziasis or schistosomiasis, a parasitic disease of the spinal cord, is a leading cause of intramedullary pathology. In the tropics, myelopathies are often accompanied by concurrent involvement of peripheral nerves, hence the term “tropical myeloneuropathies” used to describe this group of disorders (Roma´n, 1984;

*Correspondence to: Gustavo C. Roma´n, M.D., Professor of Neurology, Methodist Neurological Institute, 6560 Fannin Street, Suite 802, Houston, TX 77030, USA. Tel: þ1-713-441-1150, E-mail: [email protected]

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Table 102.1 Possible etiologies of myelopathies in the tropics Type of lesion Congenital Cerebral palsy, dysraphism, diastematomyelia, spina bifida Traumatic injury Fracture, cervical disc herniation, spondylosis, hematomyelia, syringomyelia. Cervical spondylosis is said to be rare in tropics Tumor Extradural or intradural; bony or epidural metastasis Vascular lesions Thrombosis of anterior spinal artery, arteriovenous malformations, dural arteriovenous fistula, vasculitis – lupus, Sj€ ogren’s disease, acute transverse myelitis secondary to nucleus pulposus embolism Multiple sclerosis (MS) Spinal forms of MS, Devic’s disease (optic neuritis and myelitis), postinfectious encephalomyelitis, acute transverse myelitis Inflammatory Sarcoidosis Infections Bacterial: Tuberculosis (Pott’s disease), epidural abscesses, tropical pyomyositis (Staph. aureus), arachnoiditis, syphilis, yaws, brucellosis, mycoplasma, leptospirosis, borreliosis (Lyme disease), listeria Fungal: Cryptococcus spp., aspergillosis, histoplasmosis, blastomycosis, mucormycosis, paracoccidioidomycosis Viral: Transverse myelitis from HSV-2 (genital), combined degeneration and opportunistic infections in patients with HIV infection, HTLV-I antibodies in patients with tropical spastic paraparesis (HAM/TSP), other chronic myelopathies and MS-like disease. Poliomyelitis due to motor neuron lesions in diseases caused by polioviruses and some echoviruses, arboviruses, West Nile virus, and acute hemorrhagic conjunctivitis Parasitic: Toxoplasma gondii, Schistosoma mansoni, Taenia solium Neurodegenerative disease Amyotrophic lateral sclerosis, Friedreich’s ataxia, hereditary spastic paraparesis Toxic Fluorosis Nutritional Vitamin B12 deficiency, copper toxicity Malnutrition may produce TAN, TSP, optic and hearing defects. Probably caused neurologic syndromes of POWs in the Far East during World War II Neurotoxicity Lathyrism: common cause of spastic paraplegia on the Indian subcontinent Cyanide: excessive cassava consumption, common in Nigeria and Tanzania, causes konzo and tropical ataxic neuropathy Clioquinol (Entero-vioform) caused subacute myelo-optico neuropathy (SMON) in Japan Organophosphates and pesticides: triorthocresylphosphate may cause tropical ataxic neuropathy Other problems: familial paraplegia, syringomyelia (Modified from Roma´n, 1989, p. 525.) HIV, human immunodeficiency virus; HTLV-I, HTLV-1, human T cell lymphotropic virus type 1; HSV, Herpes simplex virus; HAM/TSP, HTLV1-associated myelopathy/tropical spastic paresis; POWs, prisoners of war; TAN, tropical ataxic neuropathy; TSP, tropical spastic paraparesis.

Roma´n et al., 1985). In addition, endemic or epidemic clusters of myelopathies or myeloneuropathies occur with high prevalence almost exclusively in tropical regions. The latter are characterized by funicular lesions of the spinal cord accompanied by axonal, predominantly sensory peripheral neuropathy that may be due to nutritional or toxic causes and a number of other possible etiologies.

HISTORICAL ASPECTS The high prevalence of endemic myeloneuropathies in tropical and subtropical regions has been recognized for centuries (Table 102.2). However, reports from Africa, the Far East, and the West Indies remained unnoticed until World War II, when myeloneuropathies in prisoners of war detained in tropical camps made

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Table 102.2 Historical description of epidemic myelopathies and myeloneuropathies From Roman (1985) and Roman et al. (1985) Year

Place

Author

Clinical features

Probable etiology

50 BC 1671

Greece Germany

Palsy of legs Leg palsy

Lathyrism Lathyrism

1672 1826

Jamaica India

Dioscorides Georg, Duke of W€ urttemberg Ellwood Grierson

Palsies Burning feet

1888, 1897 1898 1917

Jamaica Cuba Jamaica

Strachan Ma´dan Scott

Multiple neuritis Optic neuropathy Ataxic myelopathy

1930 1930

Africa USA

Moore Several

1932

Africa

Stannus

1936–1939

Spain

1938

Congo

Garcı´a Jime´nez, Grande Covia´n Trolli

Optic neuropathy Jamaica ginger neuropathy Pellagra, painful neuropathy Neuromyelopathies

Lead from rum casks Vitamin/mineral deficiency Arsenic Malnutrition Post-conjunctivitis (viral?) Malnutrition TOCP

1942–1945

Far East

Cruickshank

1956 1962

Jamaica Senegal

Cruickshank Collomb et al.

1965 1968

South Africa Nigeria

Cosnett Osuntokun

Spastic paraplegia Sensorimotor neuropathy Spastic myelopathy Ataxic neuropathy

1969

South India

Mani et al.

Spastic paraplegia

1981 1982 1984

Colombia Seychelles Mozambique

Zaninovic et al. Kelly Cliff et al.

Spastic paraplegia Spastic paraplegia Spastic paraplegia

1987 1991–1993

Kagoshima, Japan Cuba

Osame PAHO

Spastic paraplegia Opticomyeloneuropathy

Spastic paraplegia, konzo WWII-POWs

Nicotinic acid deficiency Malnutrition, lathyrism Cyanide /cassava/ malnutrition Malnutrition/ malabsorption HTLV-1 Malnutrition HTLV-1 (?) Cyanide /cassava/ malnutrition HTLV1(?), lathyrism (?) HTLV-1 HTLV-1 Cyanide /cassava/ malnutrition HTLV-1 Malnutrition

WWII-POWs, World War II prisoners of war; HTLV-I, human T cell lymphotropic virus type 1; TOCP, tri-ortho-cresil-phosphate; PAHO, Pan American Health Organization.

neurologists aware of the relationships existing between tropical climate and the epidemic occurrence of these conditions in situations characterized by nutritional deprivation combined with tropical malabsorption caused by toxicogenic bacterial infections. Roma´n et al. (1985) and Bruyn and Poser (2000) have reviewed the history of the endemic and epidemic forms of tropical myelopathies. The earliest reports (1672) from Jamaica described epidemic outbreaks of strange palsies among settlers and African slaves (Roma´n, 1985); in 1888 and 1897, Henry Strachan reported 510 cases of “a form of multiple neuritis prevalent in the West Indies,” observed at the Kingston Public Hospital in Jamaica; in 1898, Domingo

Ma´dan in Cuba described epidemic cases of retrobulbar optic neuropathy that he considered identical to tobaccoalcohol amblyopia, “although none of these patients drank,” and were probably associated with malnutrition. In 1917, Henry Harold Scott reported an outbreak of 21 patients with neuropathy in Spanish Town, Jamaica. In 1956, Eric K. Cruickshank, working at the Medical School of the West Indies in Mona, Jamaica, described 100 patients with “a neuropathic syndrome of uncertain origin” characterized by spastic paraparesis with minimal sensory deficits (tropical spastic paraparesis). More recently (1991–1993), an epidemic of optic neuropathy of nutritional origin affected the island of Cuba (Roma´n

G.C. ROMA´N

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1994). The tropical myelopathies have been the subject of productive research, as demonstrated by the discovery of the role of human T-lymphotropic virus type 1 (HTLV-1), the first human retrovirus, in tropical spastic paraparesis.

CLINICAL ASPECTS The large number of conditions capable of producing involvement of the spinal cord in the tropics listed in Table 102.1 can be conveniently approached from the clinical viewpoint by separating them into acute and chronic. Acute myelopathies present with onset of symptoms within hours or days; chronic myelopathy cases evolve insidiously with slow progression over months and even years. Symptoms indicative of spinal cord involvement include loss of motor, sensory, and sphincter function. The motor involvement is usually bilateral and can produce leg weakness (paraparesis), or weakness of all four limbs (quadriparesis or tetraparesis); complete loss of movement is called respectively paraplegia and quadriplegia. Pain is also an important localizing sign of spine and root pathology; lesions affecting the cervical spinal cord and roots present with cervical, suboccipital, or interscapular pain radiating to the arms while chest pain or back pain is present with lesions of thoracic or lumbosacral spinal cord, respectively. Loss of sensation to pinprick and to the tuning fork vibratory stimulation demonstrates a sensory level that allows localization of the level of the spinal cord lesion. Finally, urinary and/or stool incontinence is an important sign of spinal cord damage. The combination of acute motor loss, sensory level, and sphincter incontinence is an emergency that should be treated with absolute priority to prevent long-term disability or death. In cases of trauma, appropriate immobilization of the neck and adequate transport of the patient is mandatory in order to prevent what has been called “the second injury.” Imaging of the spine and cord with CT/MRI or myelography should be obtained as soon as possible in order to rule out compression of the cord amenable to surgical decompressive treatment complemented with steroids (intravenous methylprednisolone). The management of acute spinal cord lesions has been reviewed recently (McDonald and Sadowsky, 2002; Fogelson and Krauss, 2008).

CAUSES OF ACUTE MYELOPATHY IN THE TROPICS Most of the etiologies of acute myelopathy listed in Table 102.1 are also seen in temperate regions of the world and will not be addressed here unless some peculiar features occur in the tropics.

Trauma Trauma is one of the leading causes of disability and death worldwide. In the tropics, lack of traffic regulations and poor emergency services result in enhanced mortality and morbidity. For instance, in Nigeria, Solagberu (2002) reported the characteristics of spinal cord lesions in 39 patients; most cases (36/39) were young males (mean age 37.7 years) and traffic accidents were the main cause of injury occurring while the subjects were riding in open lorries sitting on top of their goods; the second cause was falls from kolanut trees or palms. There was high mortality (10/39), mainly among the 70% of patients with cervical cord injuries. Also in Nigeria, Olasode and colleagues (2006) described similar findings; the poor condition of the roads and reckless driving were important causal factors of spinal cord injuries. In contrast, in the Fiji Islands, Maharaj (1996) also found a male preponderance of spinal cord lesions (male/female ratio 4:1); patients were quite young, between 16 and 30 years of age at the time of paralysis. The main causes of spinal cord injuries were falls (39%), followed by motor vehicle accidents (25%), sports (20%), shallow water dive (8%), and 4% each deep sea diving and others. Among nontraumatic causes, 53% were due to unknown causes, 32% infections, 9% neoplasms, and 6% others. Of the survivors, 31% had tetraplegia and 52% had complete lesions. The incidence of secondary complications such as pressure sores and urinary infections was also found to be high when compared with other studies.

Disc herniation and spondyloarthritis Disc herniation in the tropics has been considered to be less frequent than in temperate regions, accounted for in part by the alleged protection of the generalized habit of carrying heavy loads on the head. However, as mentioned above, imaging has shown that disc pathologies remain high in the list of lesions of the spine in tropical regions. Also, incorrect diagnosis may lead to surgery in cases of osteoarticular brucellosis that may mimic disc disease as documented in Iran by Janmohammandi and Roushan (2009), who retrospectively studied 232 patients with osteoarticular brucellosis causing polyarthritis, monoarthritis, spondylitis, and sacroilitis. Galukande et al. (2005), from Uganda, found in 204 patients with low-back pain that most cases, or 62%, had mechanical causes, 19% had nerve root compression due to prolapsed intervertebral discs, and 17% had serious spinal pathology due to tuberculosis, brucellosis, fractures, and degenerative changes. According to Richens and McGill (1995), the spondyloarthropathies occur with variable frequency in the

TROPICAL MYELOPATHIES tropics. Ankylosing spondylitis is rare in tropical Africa, due to low frequency of the HLA-B27 gene, but in contrast it is seen more often in the Melanesian populations of Papua New Guinea. In the tropics, cases of infectious and reactive arthritis are relatively common. With the spread of HIV infection in Africa an increasing prevalence of reactive arthritis has been observed. Common treatable causes of acute arthritis sometimes presenting with neurologic signs are chlamydia-triggered arthritis, disseminated gonococcal infection, tuberculosis, and brucellosis.

Vascular causes of acute myelopathy Vascular lesions are relatively rare causes of acute myelopathy; these lesions include spinal cord infarction, hematomyelia, and dural arteriovenous fistula. A condition that has been reported in the tropics and mimics acute transverse myelitis is spinal cord embolism of fibrocartilaginous material from the nucleus pulposus of intervertebral discs.

NUCLEUS PULPOSUS EMBOLISM Toro et al. (1994) reported a case from Colombia of a previously healthy 16-year-old girl living in a dairy farm who was milking a cow when she experienced acute onset of very severe low-back pain radiating into her thighs. About 15 minutes later she had become completely paraplegic. On examination she exhibited a flaccid paraplegia with areflexia of lower limbs, sensory level with loss of pinprick and vibration from L1 down, perineal anesthesia with urinary incontinence, and loss of rectal tone and arreflexia. The patient eventually died from complications and postmortem examination showed ischemic infarction of the lumbar spinal cord due to arterial and venous embolization with fibrocartiaginous material from nucleus pulposus embolism. Epidemiologic features. In an extensive review of the literature Toro et al. (1994) analyzed 32 cases reported from around the world; overall, there was a female preponderance with a women to men ratio of 2.2:1. Distribution by race and ethnicity included 27 white Caucasians, three blacks, and one case each from India and Latin America (Colombia). The age of onset ranged from 13 to 77 years with a median of 38.5 years and a bimodal distribution with two peaks of age incidence, the first one among young patients with a median age of 22 years, and a second peak among postmenopausal women at a median age of 60 years. Clinical picture. The typical clinical features included a sudden onset of severe, excruciating neck or back pain accompanied by muscle weakness. In cases of cervical disc embolism the pain was interscapular radiating to the neck, chest, and abdomen. Embolism from lumbar spine discs resulted in low-back pain radiating to the legs and abdomen. Cervical-medullary lesions were

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accompanied by respiratory failure. Motor manifestations included a flaccid paraplegia or quadriplegia with areflexia of deep tendon reflexes and cutaneous reflexes. Sensory examination revealed deficits consistent with anterior spinal artery occlusion, including loss of pinprick and temperature with preserved perception of vibration of the tuning fork. Differential diagnosis. The clinical picture resembles closely a transverse myelopathy, except for the severe pain. Cerebrospinal fluid (CSF) examination is usually normal. Imaging. MR images showed swelling of the cord and increased T2 signal intensity together with collapse of the intervertebral disc space, sometimes with nucleus pulposus herniation into the adjacent vertebral body end plate. Cord lesions may include increased T2 signal, minimal contrast-enhancing foci, and hemorrhagic necrosis of the cord as a late, terminal sign. Often, the vertebral body bone marrow shows evidence of infarction from the embolism. According to Tosi et al. (1996), in a patient with clinical symptoms suggestive of spinal cord embolism, the MRI finding of cord swelling associated with a collapsed disc space at the appropriate level is almost pathognomonic of nucleus pulposus embolism to the spinal cord (Fig. 102.1). Neuropathology. Neuropathological studies have shown that the most frequent level of involvement is the cervical spine (70%) extending sometimes from the medulla oblongata to upper thoracic levels, followed by the lumbar spine (22%) extending rarely from the lower thoracic cord the sacral segments. The territories involved are equally divided between arterial occlusion in the anterior spinal artery (50%) and venous embolism (50%). In some cases a typical transverse ischemic myelopathy occurs or, more rarely, a ramollissement en crayon (pencil-shaped infarction). Pathogenesis. The nucleus pulposus is a semifluid fibrocartilaginous cushion considered to be a remnant of the embryonic notochord. Close contact of the nucleus pulposus to vertebral body venous sinusoids is postulated to establish a communication between the nucleus pulposus and the venous system of the spine including Batson’s venous plexus. Increased intraosseus pressure within the vertebral body due to acute vertical disc herniation would inject nucleus pulposus material into veins, arteriovenous shunts, and arteries resulting in spinal cord ischemia and necrosis (Fig. 102.2). Treatment. The postulated treatment includes intravenous steroids and hyperbaric oxygen.

INFECTIOUS MYELOPATHIES Infection is one of the commonest causes of acute myelopathy in the tropics. The entire spectrum of infective agents capable of causing myelopathy (Table 102.1) is quite extensive (Berger and Sabet, 2002); therefore,

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Fig. 102.1. Nucleus pulposus embolism causing extensive ischemic myelopathy. T2-weighted MRI shows intramedullary longitudinal hyperintense signal from C6 down to the conus medullaris, intersomatic disc collapses and vertebral body infarctions (C5–7/T8–10). (Reproduced from Th€one et al., 2007.)

Fig. 102.2. Proposed physiopathological mechanism of nucleus pulposus embolization of the spinal cord. Increased disc pressure leads to extrusion of the nucleus pulposus into vertebral body sinusoidal veins. From the sinusoids fibrocartilaginous material is injected into vertebral veins in Batson’s plexus. Spinal arteriovenous communications allow entrance of the material into spinal arteries causing ischemia of the spinal cord. Spinal cord veins are also embolized, often leading to arterial and venous occlusions. (Reproduced from Toro et al., 1994.)

TROPICAL MYELOPATHIES 1527 the approach to etiologic diagnosis and management as aciclovir, valaciclovir, and famciclovir used in the treatshould be epidemiologic, considering first the most comment of shingles should be used to treat VZV myelitis as mon agents in the patient’s specific region of the world. early as possible (Berger and Sabet, 2002). The following etiologic agents will be briefly discussed: ● ● ●

● ●

viruses including herpes-group viruses, rabies, and enteroviruses retroviruses: HTLV-1, HTLV-2, and HIV bacterial infections including meningomyelitis and epidural abscess due to tuberculosis, brucellosis, Lyme borreliosis, mycoplasma and neurosyphilis fungal infections: Nocardia, Cryptococcus spp. parasites including nematode infections (angiostrongyliasis, gnathostomiasis, strongyloidiasis, toxocariasis); cestodes (cysticercosis, echinococcosis); and trematodes (paragonimiasis, schistosomiasis).

Viral myelopathies This topic has been extensively reviewed by Kincaid and Lipton (2006) and Berger and Sabet (2002). Except for endemic clusters of tropical spastic paraparesis due to HTLV-1, viral infections are uncommon causes of acute myelopathy.

POLIOMYELITIS Prior to universal vaccination the most common cause of acute viral myelitis presenting as an acute flaccid paralysis used to be poliomyelitis caused by polioviruses 1, 2, and 3. Cases of acute poliomyelitis may occur following the use of Sabin polio vaccine. The Australian National Polio Reference Laboratory identified 1325 isolates from acute poliomyelitis cases between 1995 and 2000; of these, 53% were confirmed as Sabin vaccine-like polioviruses, 41% were nonpolio enteroviruses, and 6% yielded no virus or viruses other than enteroviruses (Stambos et al., 2001). Other agents capable of causing of causing anterior horn cell necrosis with asymmetric acute flaccid paralysis include coxsackieviruses A and B; enterovirus-71, for instance during epidemics of viral conjunctivitis; and flaviviruses, including West Nile virus.

HERPESVIRUSES The herpesviruses, including varicella zoster (VZV), herpes simplex type 2 (HSV-2), and cytomegalovirus (CMV) are a common etiology of encephalitis but less often a cause of myelitis. VZV remains dormant in the dorsal root ganglia after causing varicella (chickenpox). Reactivation of the virus, due most often to immunosuppression, leads to viral multiplication and to herpes zoster (shingles), complicated in rare cases with a necrotizing myelopathy (Devinsky et al., 1991). Antiviral agents such

Chronic retroviral myelopathies HUMAN T CELL LYMPHOTROPIC VIRUS-1 The only human virus capable of chronically infecting the spinal cord without causing brain involvement is the human T cell lymphotropic virus type 1 (HTLV1), the causal agent of adult T cell leukemia/lymphoma and of tropical spastic paraparesis/HTLV-1 chronic myelitis (also called HTLV-1-associated myelopathy). Gessain and Mahieux (2012) have recently reviewed the epidemiologic, virologic, and clinical aspects of this infectious myelitis; Roma´n (2003) reviewed several proposed therapies. Virology. HTLV-1, the first human retrovirus, was discovered in 1980 in a patient with cutaneous lymphoma. HTLV-1 is classified in the Retroviridae family, Orthoretrovirinae subfamily and the Deltaretrovirus genus. HTLV-1 infects CD4þ lymphoid cells and has three major genes (gag, pol and env) encoding the structural and enzymatic proteins. Rare cases of tropical spastic paraparesis are caused by HTLV-2. The double infection with HTLV-1/HIV is not infrequent in areas with high prevalence of AIDS. Epidemiology. Cases of chronic HTLV-1 myelitis have been described in the Caribbean, particularly in Jamaica and Martinique, as well as in southern Japan, Colombia, Ecuador, Chile, Brazil, the Seychelles, Iran, and in some African countries. Tropical spastic paraparesis appears to be identical to a chronic myelitis described in the southern islands of Japan (HTLV-1associated myelopathy, or HAM). In most of Africa and southern India the etiology of tropical spastic paraparesis appears to be different, and remains unknown. An estimated 10–20 million people worldwide are infected with HTLV-1. Transmission of HTLV-1 occurs by three mechanisms: (1) mother to child by breastfeeding; (2) sexual contact mainly from infected male to female; (3) via transfusion of contaminated blood products. The lifetime risk of hematologic or neurologic involvement among HTLV-1 carriers is 0.25–3%. Clinical features. HTLV-1 myelitis occurs in adults with onset at 40–50 years of age; it is more common in women than in men. HTLV-1 myelitis causes a chronic spastic paraparesis syndrome with minor sensory signs; it appears to be quite uniform worldwide, with minor regional variations. Onset of the disease is gradual in more than 60% of cases with gait disturbance and urinary symptoms. In most patients, one leg is affected more than the other at onset. Progression usually is slow

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and indolent, sometimes reaching a plateau and remaining at that level for several years. All patients have weakness of the legs, back pain, leg numbness, and dysesthesias of the feet. Sphincter involvement and bladder dysfunction are manifested mainly by increased urinary frequency, urgency and incontinence; constipation and penile impotence also occur. The core of the syndrome on neurologic examination is defined by the presence of spastic paraparesis or paraplegia, increased knee reflexes, crossed adductor responses, ankle clonus, and extensor plantar responses indicative of bilateral pyramidal tract lesion affecting the lower limbs. Spasticity is moderate, predominating on the thigh adductors and to a lesser degree on the thigh extensors and gastrocnemius muscles. Motor weakness is proximal and affects mainly gluteus medius and iliopsoas muscles. Gait is typically slow and scissoring, with dragging and shuffling of the feet. The severe spasticity of lathyrism, with lurching gait on the ball of the foot and toes is not seen. Most patients ambulate with minimal support, but one-third are bedridden either as a result of rapid onset of the paraplegia or after long progression of the disease. Up to half the patients exhibit brisk reflexes in the upper limbs, and one-sixth have snout and brisk mandibular reflexes. There are minimal signs of involvement of the posterior columns but other sensory deficits, such as thoracic sensory level of loss of pain sensation, are not commonly present. Higher mental functions are normal. Examination of the cranial nerves is usually normal, except in Jamaica, where retrobulbar optic neuropathy and deafness occurred in 15% and 7%, respectively. Cerebellar signs, in particular intention tremor and dysmetria, have been observed in up to 20% of patients. Rare cases manifested as a spinocerebellar syndrome have been reported (Castillo et al., 2000). In addition to paresthesias in the feet, mild decrease of vibratory perception distally in the feet is found, usually without loss of proprioception. Ankle reflexes are absent in about 25%, and stocking-type loss of sensation in a pattern suggestive of peripheral neuropathy has been described in a third of patients. Laboratory findings. Peripheral blood may show atypical T lymphocytes with convoluted nuclei (“flower cells”). CSF shows a mild pleocytosis, sometimes with “flower cells,” mild increase in proteins, elevated IgG index, and oligoclonal bands due to local synthesis of anti-HTLV-1 antibodies. HTLV-1 antibodies are also present in the serum of the patients, but titers are typically higher in the CSF. Enzyme-linked immunoabsorbent assay (ELISA) is commonly used, but positive titers require confirmation with recombinant Western blot assay showing reactivity to gag (p19 or p24) and env (gp21 or gp46) gene products. Intrathecal immune

Fig. 102.3. T2-weighted sagittal MRI demonstrating atrophy of the spinal cord in a chronic case of HTLV-1 myelitis. (Reproduced from Howard et al., 2003.)

response against env gp21 synthetic peptides can be detected in the CSF by Western blot analysis. A high HTLV-1 proviral load is observed in the blood. Mild to moderate increase of proteins may be present in the CSF. Imaging. In the acute stage, MRI of the spinal cord may show localized spinal cord swelling of the lumbosacral segment, or high-intensity signal on T2-weighted images in the thoracic spinal cord, followed by atrophy, usually localized to the thoracic region (Fig. 102.3). Nonspecific hyperintense foci on T2-weighted signals may be found in the periventricular white matter of the brain. Neuropathology. On postmortem examination, HTLV-1 myelitis is characterized by chronic progressive myelin loss and funicular axonal degeneration in the white matter of the spinal cord, with chronic perivascular infiltrates. Optic nerve demyelination and foci of brain leukoencephalopathy may also be seen. It has been suggested that HTLV-1-infected CD4 þ T cells migrate to

TROPICAL MYELOPATHIES the central nervous system, and cytotoxic CD8þ T cells would produce cell-mediated cytotoxic demyelination. Differential diagnosis. Other causes of progressive myelopathy should be ruled out including spinal cord compression, tumors, bilharziasis, B12 deficiency, HIV infection, primary progressive multiple sclerosis, Lyme disease, and konzo, a form of spasticity prevalent in Africa and associated with excessive consumption of cassava and chronic cyanide intoxication. Treatment. Therapy remains symptomatic using medications to improve spasticity; transient improvement with corticosteroids has been documented. The combination therapy used in HIV infection (AZT þ 3TC) such as Combivir® (150 mg lamivudine plus 300 mg zidovudine: one tablet twice daily) could decrease HTLV-1 viral load and improve neurologic function. However, although no clinical experience with this therapy is available, Pot et al. (2006) reported near-complete radiologic and clinical recovery of a patient with HTLV-1 myelitis and Sj€ ogren syndrome treated with combined antiretroviral treatment (lamivudine and tenofovir) plus immunosuppressant therapy with prednisone and mycophenolate mofetil. Public health measures for HTLV-1/2. Public health programs for the control of HTLV-1/2 infection in endemic populations should be undertaken to prevent the high morbidity associated with these infections. These programs require several measures that can be implemented along with HIV control programs, as follows: 1. 2. 3. 4.

prenatal control of pregnant women to discourage breastfeeding among HTLV-1/2-positive women blood bank screening of all donors clean-needle programs for intravenous drug users safe-sex programs to encourage condom use.

HUMAN IMMUNODEFICIENCY VIRUS Myelopathy in patients infected with human immunodeficiency virus (HIV) occurs either during the acute phase of seroconversion or more commonly during the symptomatic phase of AIDS when infected patients may develop a vacuolar myelopathy resembling subacute combined degeneration from vitamin B12 deficiency; finally, infectious myelitis may occur in immunosuppressed patients as a result of infections with a potentially large number of infectious agents and as a result or other noninfectious conditions (Table 102.3). Vacuolar myelopathy According to Berger and Sabet (2002), vacuolar myelopathy is the most common form of spinal cord disease in HIV-infected individuals; however, it is under-recognized clinically since the symptoms of lower

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Table 102.3 Myelopathies associated with HIV infection Infectious Viral HIV Acute transient myelopathy occurring at the time of seroconversion Chronic progressive myelopathy (vacuolar) HTLV-1 Cytomegalovirus Herpes simplex Herpes zoster Bacterial Epidural abscess Mycobacterium tuberculosis Treponema pallidum Fungal Cryptococcus neoformans Other Parasites Toxoplasma gondii Noninfectious Multiple sclerosis-like illness Tumors Plasmacytoma Spinal cord astrocytoma Other Epidural hemorrhage secondary to thrombocytopenia Vascular injury secondary to vasculitis HIV, human immunodeficiency virus; HTLV-1, human T cell lymphotropic virus type 1 (Adapted from Berger and Sabet, 2002.)

extremity weakness and paresthesias are often attributed to general debility and concomitant peripheral neuropathy of the patient with AIDS. In some geographic areas, such as South Africa, Brazil, and the Caribbean, myelitis is seen in patients coinfected with HIV/HTLV-1. Herpes zoster virus (VZV) coinfection with HIV is also a common cause of myelopathy. Clinical manifestations. The vacuolar myelopathy of HIV presents with spastic paraparesis, but with more leg weakness than spasticity. Rarely, asymmetry of leg weakness, monoparesis or quadriparesis may be seen. Sensory gait ataxia is common and dysmetria may be present. Weakness may be slight on muscle strength testing but hyperreflexia of the lower extremities and extensor plantar responses are usually present. In patients with concomitant peripheral neuropathy deep tendinous reflexes may be diminished or absent, particularly at the ankles. Vibratory and position senses are disproportionately affected in comparison with pinprick, temperature, or light touch, suggesting dorsal column impairment. Presence of a superimposed peripheral neuropathy is frequent. Impotence and incontinence are commonly seen.

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Neuropathology. On neuropathology examination there is loss of myelin and spongy degeneration involving mostly the lateral and posterior columns. There is microvacuolization of the white matter of the spinal cord with a honeycomb appearance resulting from intramyelin swelling, associated with lipid-laden macrophages, similar to that seen in subacute combined degeneration of the spinal cord from vitamin B12 deficiency. Axons are preserved except in areas of marked vacuolization. Microglial nodules may be seen in the gray matter of the cord along with central chromatolysis of anterior horn motor cells. The postulated cause is a defect in the vitamin B12-dependent transmethylation pathway; or a combination of immune-mediated injury to myelin and oligodendroglia with lack of repair mechanisms due to a deficiency of S-adenosylmethionine. Differential diagnosis. Concurrent infection with other viral, bacterial, fungal or even parasitic agents must be ruled out. Neurosyphilis is particularly common in patients with AIDS and myelopathy. The prevalence of vacuolar myelopathy is expected to decrease with better treatment of AIDS.

Bacterial myelopathies Mycoplasma pneumoniae and other agents may cause parainfectious myelopathies. Other bacterial conditions include scarlet fever, pertussis, whooping cough and pneumococcal pneumonia. A myelitis presenting as a Brown-Se´quard syndrome has been described with cat scratch disease due to Bartonella henselae (Berger and Sabet, 2002).

Fig. 102.4. Tuberculous spondylitis and epidural abscess at T4 on sagittal MRI of the spine on T2-weighted images. (Reproduced from Bale´riaux and Neugroschl, 2004.)

TUBERCULOSIS The most frequent form of involvement of the spinal cord in tuberculosis is Pott’s disease, or tuberculous paraplegia. The topic has been extensively reviewed by Gautam et al. (2005) in Nepal and by Turgut (2001) in Turkey. The neurosurgical experience in Turkey included 694 patients; most of the cases occurred in young adults with a mean age of 32 years, equally distributed between men and women. The presenting symptoms were leg weakness (69%), gibbus (46%), pain (21%), and palpable mass (10%). Tuberculosis is caused by Mycobacterium tuberculosis, a highly infectious agent that causes predominantly pulmonary tuberculosis; contagion is mediated by aerosols from cough and is favored by crowed living conditions particularly among socially disadvantaged groups, including the unemployed, the homeless sleeping in crowded shelters, and migrant populations with poor nutrition. Tuberculosis affecting the spine is seen in only 10% of subjects with tuberculosis and perhaps only 1% develop paraplegia and death. The lesion begins as tuberculous osteomyelitis of the vertebral body with erosion

and anterior collapse of the vertebral body (Figs 102.4 and 102.5), followed by formation of a gibbus and a cold abscess that eventually produces compression of the cord and neighboring nerve roots. Preservation of disc spaces is one of the hallmarks of spinal tuberculosis. The most common localization is in the thoracic region (56%), involving the vertebral body, followed by the lumbar region (23%), the thoracolumbar region (17%), and the cervical region (4%). Indications for surgical treatment include spine deformity, neurologic deficit, intractable pain and abscess enlargement despite medications. Anti-TB chemotherapy includes combinations of rifampicin, isoniazid, pyrazinamide, and either ethambutol or streptomycin administered for 2–6 months, followed by rifampin and either isoniazid or ethambutol for a total of 6–18 months. Decompressive surgery plus anti-TB chemotherapy remains the best mode of therapy for Pott’s disease. Neurologic involvement due to Pott’s disease can be relatively benign if urgent decompression is performed at the onset of leg weakness.

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Fig. 102.5. CT scan demonstrating destruction and fragmentation of the vertebral body and paravertebral soft tissue mass with paravertebral calcifications consistent with cold abscess in Potts’ disease. Reprinted with permission from JBR-BTR. (Reproduced from De Backer et al., 2005.)

BRUCELLOSIS Brucellosis is a systemic infectious disease, caused by Gram-negative bacilli belonging to the genus Brucella. This disease is a zoonosis transmitted to humans from infected animals such as goats, sheep, cows, and camels (B. melitensis, B. abortus, B. ovis). High-risk areas include the Middle East, the Arabian peninsula, the Mediterranean basin (Portugal, Spain, southern France, Italy, Greece, Turkey, North Africa), Mexico, Central and South America, Eastern Europe, Asia, Africa, and the Caribbean (Corbel, 1997). For instance, brucellosis is endemic in Turkey and during the last decade over 9000 cases/year were reported (incidence 14/100 000); screening of the general population for seropositivity (Wright test, positive at > 1/160) revealed a seroprevalence of 1.8% (G€ org€ ul€ u et al., 2006). Infection occurs in most cases by consumption of unpasteurized milk, cheese, or dairy products from infected animals. Infection from aspiration of bacteria in aerosols or from skin abrasion also occurs among veterinarians, laboratory workers, butchers, and hunters. The clinical manifestations include malaise, sweats, anorexia, headache, myalgia, and back pain usually with prolonged intermittent fever (Malta’s undulant fever); in addition, gastrointestinal, respiratory, arthritis, dermal, ocular, or neurologic manifestations may occur. Spondylitis is one of the most frequent and serious complications of the disease. Brucella lesions of the spine occur in up to 50% of cases.

Fig. 102.6. Brucellosis with formation of a cervical epidural abscess (black arrow) extending from C5 to C8. Sagittal MRI of cervical spine on T1-weighted images. (Reproduced from G€ org€ ul€ u et al., 2006.)

Lesions may affect all levels but most commonly involve the lumbar spine at the L4–5 level. Cervical involvement occurs in 6–10% of cases (Song et al., 2012). Spinal epidural abscess is relatively rare (G€org€ ul€ u et al., 2006). The lesion begins as spondylodiscitis with a progressive abscess that involves adjacent vertebral bodies, prevertebral soft tissues, and the epidural space causing compression of the spinal cord and nerve roots (Fig. 102.6). The diagnosis needs to be supported by laboratory tests including serum serology and blood culture during the acute phase. Isolation in blood or tissue is successful in 50–70% of cases. Treatment of spinal complications of brucellosis requires prompt surgical decompression and drainage of the abscess followed by antibiotic therapy. Treatment of acute brucellosis in adults requires a combination of rifampicin 600–900 mg and doxycycline 200 mg daily for a minimum of 6 weeks. A high relapse rate occurs with single antibiotics. Intramuscular streptomycin with oral tetracycline was recommended in the past due to fewer relapses. Complications of brucellosis, such as myelitis, meningoencephalitis, or endocarditis, require combination

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therapy with rifampicin, a tetracycline, and an aminoglycoside (Corbel, 1997). Resolution of brucellosis is indicated by seroconversion, negative blood cultures, improvement of clinical symptoms such as fever and CT/MRI imaging findings, as well as a decrease in inflammatory markers (ESR, CRP).

SPINAL EPIDURAL ABSCESS Infections of the spine may involve the vertebral body (spondylitis), the intervertebral disc (spondylodiscitis), the ligaments and paravertebral soft tissues, the epidural space (epidural abscess), the meninges and the subarachnoid space, and very rarely the spinal cord, causing infectious myelitis or spinal cord abscesses (Bale´riaux and Neugroschl, 2004). The clinical manifestations include pain and motor-sensory deficits in the appropriate dermatomal distribution. In patients with diabetes mellitus fever may be absent and one of the few indicators of the presence of the abscess is the increase in sedimentation rate and other inflammatory markers. Hematogenous dissemination from a primary source of invasive staphylococcal disease is the most common mechanism for the development of an epidural abscess. In children, the high vascularization of the disc explains the fact that discitis constitutes the primary spinal infectious lesion with secondary extension to the adjacent vertebral bodies. Iatrogenic infections following lumbar puncture, epidural anesthesia or surgical interventions remain common, as recently reported by Nwadinigwe and Anyaehie (2011) in Nigeria. According to Bale´riaux and Neugroschl (2004), the most common cause of spinal epidural abscesses is Staphylococcus aureus found in 55–80% of cases. Other causal organisms include Streptococcus, Pneumococcus, Enterococcus, Escherichia coli, Salmonella, Pseudomonas aeruginosa, and Klebsiella. Granulomatous infections are mainly due to Mycobacterium tuberculosis, Brucella spp., fungi, and parasites. CT is an excellent technique for the detection of bony erosions as well as for demonstrating infiltration of perivertebral regions; also, the MRI is critical for demonstration of lesions compressing spinal cord (Fig. 102.7) and nerve roots (Bale´riaux and Neugroschl, 2004). Lesions that fail to compromise the intervertebral disc or vertebral end plates include granulomatous osteomyelitis, metastasis, lymphoma, and, less likely, atypical presentation of pyogenic vertebral osteomyelitis (Song et al., 2012). The treatment includes surgical decompression, drainage of the abscess, and appropriate antibiotic treatment. Spinal epidural abscess due to Nocardia asteroides, a bacterial organism that grows readily in culture media used for fungus, usually

Fig. 102.7. Cervical epidural abscess in a patient with Staphylococcus aureus septicemia. Sagittal cervical MRI on T2weighted images demonstrating the posterior location of the abscess. (Reproduced from Bale´riaux and Neugroschl, 2004.)

responds to treatment with a triple antibiotic intravenous regimen consisting of trimethoprim/sulfamethoxazole, amikacin, and ceftriaxone (Harvey et al., 1998). Among the fungal organisms, Batra et al. (2011) recently reported in India a case of acute cauda equina syndrome due to Aspergillus fumigatus that improved after surgical treatment and oral itraconazole.

Spirochetal myelopathies The family Spirochaetaceae has three major genera: Treponema, Borrelia, and Leptospira; morphologically, these agents are spirochetes characterized by the corkscrew-like appearance and active motility with an axial filament. All three genera infect the nervous system producing meningoencephalitis, infectious myelitis, meningoradiculoneuritis and peripheral nerve inflammation (Estanislao and Pachner, 1999).

LYME DISEASE The spirochete Borrelia burgdorferi was identified as the cause of Lyme arthritis in 1983 (Burgdorfer et al., 1983; Burgdorfer, 1998); Lyme arthritis is manifested

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Fig. 102.8. Acute neuroborreliosis presenting as myelo-meningoradiculopathy. Gadolinium-enhanced sagittal MRI of the spine showing meningeal enhancement at cervical (A), thoracic (B) and lumbosacral (C) levels. (Reproduced from Chang et al., 2010.)

by a typical skin rash called erythema chronicum migrans, followed by dissemination of the spirochete to other organs with arthritis, myocarditis, cardiac arrhythmias (atrioventricular block), myalgias, and neurologic disease. History. In 1921, Afzelius described erythema chronicum migrans in Europe; Garin and Bujadoux (1922), in France, first reported cases of meningoradiculoneuritis and tick paralysis; in 1941, in Germany, Bannwarth described tick-borne chronic lymphocytic meningitis with polyneuritis and arthritis. Epidemiology: Lyme borreliosis is a zoonosis of deer transmitted to humans by infected ticks. B. burgdorferi has been identified in ticks in South America and cases of Lyme disease have been reported in Sa˜o Paulo, Brazil (Yoshinari et al., 1993), Colombia, and Bolivia. Cases have been reported also in North Africa, including Morocco, Algeria, Egypt, and Tunisia (Bouattour et al., 2004) as well as in South Africa (Fivaz and Petney, 1989) and Kenya, East Africa (Jowi and Gathua, 2005). Clinical features. Neurologic manifestations of neuroborreliosis include facial paralysis, lymphocytic meningitis, often with minimal symptoms. Meningeal inflammation indicates treponemal dissemination into the central nervous system and must be treated energetically with intravenous antibiotics. One of the most common manifestations of acute neuroborreliosis is meningoradiculopathy (Chang et al., 2010), manifested by burning back pain, spasms, and shooting pains in the limbs or the trunk indicating root invasion by Borrelia. Gadolinium enhancement of leptomeninges can be observed with MRI (Fig. 102.8). Chronic infection of the central nervous system may be manifested by cognitive and neuropsychiatric symptoms. Neuroborreliosis may be manifested by a myelopathy (Reik et al., 1979). Diagnosis. The diagnosis is based on a history of skin lesions (erythema migrans), lymphocytosis in the spinal fluid, and positive antibodies to B. burgdorferi by

enzyme-linked immunosorbent assay (ELISA) or immunofluorescence assay (IFA) confirmed by Western blot. CSF shows pleocytosis with preponderance of lymphocytes or monocytes, elevation of protein between 50 and 300 mg% with increased albumin and immunoglobulin concentrations; IgG, total protein, and the IgG/albumin ratio can be high or normal. Oligoclonal bands may be present with specific antibodies directed against B. burgdorferi. Treatment. Given the early treponemal invasion of the nervous system the recommended treatment is with intravenous cephalosporins or penicillin for 2–3 weeks using, for instance, penicillin G 20 million Units/day every 4 hours. Third-generation cephalosporins may be better alternatives to penicillin due to their long half-life, high serum levels for longer periods, good penetration of the blood–brain barrier and high CSF concentrations. Ceftriaxone administered intravenously or intramuscularly at 1–2 g twice a day for 14 days has resulted in clinically defined cure. Oral doxycycline 200 mg daily for 14 days is also cost-effective and adequate.

NEUROSYPHILIS The causative organism of neurosyphilis is Treponema pallidum; the clinical expression of syphilis can be divided into early manifestations (primary and secondary syphilis) and late (tertiary) neurosyphilis. Early infection of the nervous system occurs weeks to years after the primary infection and is characterized by involvement of the meninges and blood vessels; it includes asymptomatic neurosyphilis, acute syphilitic meningitis, and meningovascular syphilis. Late or tertiary syphilis causes parenchymal involvement of brain and spinal cord and is manifested by tabes dorsalis and general paresis. Epidemiology. Timmermans and Carr (2004) have reviewed the recent experience with neurosyphilis in

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the Western Cape province of South Africa on 161 patients: 82 presented with combinations of delirium and dementia and other neuropsychiatric conditions, and the remainder presented with stroke (24), spinal cord disease (15), and seizures (14). Age at presentation ranged from 36 to 43 years. Cerebrospinal fluid (CSF) Veneral Disease Research Laboratory (VDRL) test was positive in 73% of cases; the remaining cases had positive treponemal test in the CSF. Tabes dorsalis is the only form that declined in the antibiotic era. However, with the increase in HIV-positive population and AIDS the number of cases of neurosyphilis appears to have increased in population-based seroprevalence studies in Africa, particularly Tanzania (Mosha et al., 1993) and Uganda (Hudson et al., 1988). Syphilic myelopathy. Involvement of the spinal cord includes tabes dorsalis, meningomyelitis, and spinal vascular syphilis usually accompanying other forms of neurosyphilis. The spinal cord neuropathology includes meningovascular and parenchymatous lesions. Intraspinal gummas and compression of the cord by syphilitic hypertrophic pachymeningitis or by vertebral lesions resulting from syphilitic osteitis may also occur. Clinical symptoms. Tabes dorsalis presents with typical pain (lightning pains) characterized by bouts of severe jabbing and lancinating pain in the lower extremities. Tabes dorsalis has the longest latent period between primary infection and onset of symptoms, ranging from 3 to 47 years (average, 21 years). In comparison with asymptomatic and meningovascular neurosyphilis, the frequency of spinal and cerebral forms of tertiary syphilis has decreased in the antibiotic era. Also important is the increase of early neurosyphilis in HIV-positive patients that fail therapy for primary syphilis. Treatment of syphilis and neurosyphilis in the HIV-positive population indicates that there is often failure to eradicate T. pallidum or to clear completely the organism from sanctuary sites in the nervous system and the eye, increasing the risk of neurosyphilis. Syphilitic meningomyelitis presents with progressive paraparesis, usually asymmetric, with spasticity, global sensory involvement in the legs, brisk reflexes, ankle clonus and Babinski sign. Syphilitic meningomyelitis may occur concurrently with the skin rash of secondary syphilis (Strom and Schneck, 1991). Negative VDRL but positive fluorescent treponemal antibody absorbed (FTA-ABS) test could occur; CSF shows mild pleocytosis and elevated proteins; usually there is good response to antibiotic treatment (Fisher and Poser, 1977). Rarely, neurosyphilis may present as acute transverse myelitis (Lowenstein et al., 1987). Neuropathology. The main lesions in tabes dorsalis (Fig. 102.9) involve the posterior spinal roots and dorsal columns with demyelination, particularly of the

Fig. 102.9. Typical lesions of tabes dorsalis. Notice atrophy of dorsal columns on the myelin stain. (Reproduced from Toro et al., 1983.)

fasciculus gracilis, the root entry zone, and Lissauer’s tract, with astrocytosis, fibrosis and vascular damage. In syphilitic meningomyelitis pathological examination reveals thickened meninges, with chronic meningitis and vascular lesions (endarteritis) of medium and small vessel with plasma cell and lymphocytic perivascular cuffing. Diagnosis. Examination of the CSF is mandatory, with presence of pleocytosis with predominant lymphocytes or monocytes, increased protein, and a reactive CSF VDRL test; negative VDRL but reactive CSF FTA-ABS test is diagnostic of neurosyphilis. Treatment. For neurosyphilis the US Centers for Disease Control and Prevention (CDC) recommends highdose intravenous penicillin G sodium (3–4 million Units intravenously every 4 hours for 10–14 days) or a 10–14 day combination of intramuscular penicillin G procaine (2.4 million Units per day) with oral probenecid (500 mg by mouth every 6 hours) followed by intramuscular benzathine penicillin G, 2.4 million Units per week for 3 weeks. HIV-positive patients with reactive VDRL should have a lumbar puncture 6 months after treatment.

BORRELIOSIS Borrelia spp. are spirochetal organisms transmitted to humans by lice or ticks. According to Estanislao and Pachner (1999), relapsing fever is caused by several species of Borrelia. The epidemic form, called louse-borne relapsing fever, is caused by B. recurrentis transmitted by the human body louse Pediculus humanus; this infection is prevalent in East Africa. The endemic form is caused by several species of Borrelia transmitted by tick vectors. As the name indicates, these conditions present with intermittent, relapsing fever. Neurologic manifestations include a meningeal syndrome, facial palsy, and cranial nerve involvement, encephalitis, seizures, extreme somnolence, hemiplegia, aphasia, ataxia, extrapyramidal symptoms, and neuropsychiatric

TROPICAL MYELOPATHIES 1535 abnormalities. Involvement of the spinal cord as myelorsplenomegaly, and skin rash. In the late stage chronic adiculitis is rare (Estanislao and Pachner, 1999). inflammation of small and large intestine, liver, or urinary bladder with granuloma formation and portal hypertension occurs. Fungal myelopathies Neurologic involvement occurs mainly during the According to Berger and Sabet (2002), involvement of early postinfective stage and can affect the brain (meninthe spinal cord with fungal infection is rare. Compresgoencephalitis) or the spinal cord (myelitis and myelorsive myelopathy may result from vertebral osteomyelitis adiculitis). Schistosoma ectopic eggs reach the CNS but fungi such as Blastomyces, Coccidioides, Cryptothrough retrograde venous flow into the Batson venous coccus, and Aspergillus may invade the spinal epidural plexus formed by vertebral epidural valveless veins, space, producing granulomatous meningitis. Spinal cord which connect the veins of the spinal cord with the infeinfarction due to meningovascular inflammation may rior venae cava, deep iliac veins, and portal venous sysalso occur. tem. Embolic ova may also reach the brain localizing in the cortex, subcortical white matter, basal ganglia, and Parasitic myelopathies internal capsule. Neuropathology shows typical Schistosoma eggs with minimal or no histologic reaction in lepBILHARZIASIS (SCHISTOSOMIASIS) tomeninges, brain parenchyma, and choroid plexus. The most common cause of acute myelopathy in adults Granuloma lesions rarely develop in the brain but focal in the tropics is bilharziasis due to spinal cord involveor diffuse vasculitis may occur. In contrast, granulomament by Schistosoma haematobium in Africa and the tous reaction around the eggs is found in the conus Middle East, or by S. mansoni in the Caribbean, Venezumedullaris and in the spinal cord (T12 to L1 levels), causela, and Brazil. This parasitic disease is caused by treming radicular and cauda equina inflammation and atode blood flukes of the genus Schistosoma (Del Brutto edema. Vasculitis of the anterior spinal artery has been et al., 2002; Roma´n, 2011). Larval forms of the parasites suggested as the substrate for vascular forms. (cercariae) released from a freshwater intermediate snail Clinical features. Schistosomal encephalitis presents host, pierce and penetrate human skin or mucosal surwith seizures, focal findings, intracranial hypertension faces with invasion of the bloodstream, usually while or encephalitis. Cerebral bleeding and subarachnoid the human host swims in a pond or a river. In the body, hemorrhage may occur. The differential diagnosis of the larvae develop into schistosomula and adult schistoschistosomal encephalopathy should include cerebral somes, which live in the blood vessels. malaria, bacterial meningitis, and viral encephalitis. Epidemiology. According to the World Health OrgaSchistosomal myelopathy. S. mansoni and S. haemanization (WHO), schistosomiasis is a major health probtobium involve the spinal cord more frequently than the lem in the tropics with some 700 million people brain; about 2.6% of patients with chronic S. mansoni worldwide exposed to infested water because of agriculinfection develop myelitis. The conus medullaris is the tural, domestic, and recreational activities, with more most common site of involvement producing an intramethan 207 million people infected worldwide (85% in dullary granuloma characterized clinically by complete Africa); most live in poor communities without flaccid paraplegia with areflexia, urinary and rectal access to safe drinking water and adequate sanitation. incontinence, impotence, sensory disturbances and lumThe prevalence of cerebral and spinal schistosomiasis bosacral pain. Other neurologic syndromes include acute is unknown. transverse myelitis, spastic paraplegia, painful lumbosaMicrobiology. Schistosoma mansoni, Schistosoma cral radiculopathy with backache, and cauda equina haematobium and Schistosoma japonicum cause human syndrome. disease. Female Schistosoma worms living inside the Neuroimaging. Myelography may reveal partial or veins lay large numbers of eggs in the inferior mesencomplete spinal cord block with intramedullary cord teric (S. mansoni) and superior mesenteric (S. japoniswelling and thickening of the roots of the cauda equina. cum) veins, and in the venous plexuses of the urinary MRI in schistosomal myelitis demonstrates mild bladder (S. haematobium). The eggs of the parasite cause enlargement of the spinal cord, swelling of the conus delayed hypersensitivity host reaction that produces the medullaris, and areas of T2 hyperintensities with intrasigns and symptoms of the disease. medullary enhancement after gadolinium injection Pathogenesis. Skin penetration by cercariae produces (Fig. 102.10). initial fever and pruritus; 3–6 weeks later the female Diagnosis. Schistosomiasis of the spinal cord can be Schistosoma worms begin releasing eggs (early postindiagnosed based on clinical presentation (acute flaccid fective stage) resulting in Katayama syndrome with paraplegia, myeloradicular painful syndrome, and fever, lymphadenopathy, eosinophilia, diarrhea, cauda equina syndrome) plus epidemiologic data such

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Fig. 102.10. Spinal schistosomiasis. Coronal (A) and sagittal (B) T1-weighted MRI of the spine with gadolinium contrast showing enlargement of the conus medullaris, and patchy contrast enhancement (large arrow) punctuated by focal nodular enhancement (small arrows) at the lower cord and cauda equina roots from schistosomal granulomas. (Reproduced from Ferrari et al., 2008.)

as history of travel or exposure to Schistosoma by bathing or swimming in fresh water in endemic regions. Laboratory confirmation includes demonstration of Schistosoma antibodies in serum and/or CSF by means of an ELISA test. The diagnosis can be suggested by typical findings on MRI or CT scan, and by patient recovery with treatment. Neurosurgical biopsy with histopathologic study of spinal lesions confirms the diagnosis. Patients with schistosomal myelopathy rarely have clinical evidence of systemic schistosomiasis. CSF shows mild lymphocytic pleocytosis, elevation of proteins, presence of eosinophils, increased IgG index, and oligoclonal bands. Biopsy of rectal mucosa and examination of stools and urine may reveal Schistosoma eggs in about 25% of patients. Differential diagnosis. Tumors, bacterial and fungal infections, and other parasitic diseases such as paragonimiasis, echinococcosis, cysticercosis, and extradural dracunculiasis are other helminthic infections that may present with cerebral mass lesions or spinal cord disease

and peripheral eosinophilia should be considered in the differential diagnosis. Treatment. A combination of schistosomicidal drugs, steroids, and surgery is currently recommended (Lambertucci et al., 2007). Praziquantel results in parasitological cure in more than 70% of patients with schistosomal myelopathy. Doses between 40 and 60 mg/kg/day are used for 14 days, in combination with prednisone or dexamethasone. Oxamniquine and metriphonate are also schistomicidal. Surgical approach includes decompressive laminectomy in cases with severe compression or CSF block on myelography, mass exeresis, and liberation of roots in patients with acute myelitis that continue to deteriorate despite clinical treatment.

NEUROCYSTICERCOSIS Involvement of the spinal cord and roots by larvae of the pig tapeworm Taenia solium is relatively infrequent, even in endemic places. Human infection occurs from

TROPICAL MYELOPATHIES human-to-human transmission of fertilized T. solium eggs from a human carrier of intestinal taenia. Humans become intermediate hosts in the life cycle of T. solium by ingesting Taenia eggs due to fecal contamination of water or food. Failure of intestinal Taenia carriers to wash their hands after defecation is the most common source of infection. Ingested eggs hatch into oncospheres in the intestine, cross the intestinal wall, enter the bloodstream, and are carried into the tissues of the host where the cysticerci develop. Epidemiology. Cysticercosis is the most common helminthic disease of the nervous system and a frequent cause of neurologic disorders in tropical areas of Latin America, Africa, and Asia accounting for about 50 000 deaths per year; survivors are left with irreversible brain or spinal cord damage. Cysticercosis can be prevented with hand washing, clean water, and environmental sanitation. Cysticercosis is becoming increasingly prevalent in industrialized countries because of travel to diseaseendemic areas and migration of tapeworm carriers and people infected with the disease. According to Wallin and Kurtzke (2004), in the US a total of 1494 patients with neurocysticercosis (NCC) were reported between 1980 and 2004, making it one of the most important emergent diseases of the nervous system. In this series, the frequency of manifestations included seizures (66%), hydrocephalus (16%), and headaches (15%) due to parenchymal NCC brain lesions (91%), and the remainder had ventricular cysts (6%), subarachnoid cysts (2%), and spinal cysts (0.2%). Pathogenesis. Cysticerci are found in the brain parenchyma, the subarachnoid spaces, the ventricular system, the eye, the spinal cord, and intrathecal nerve roots. Although many cysticerci may fail to elicit a foreign-body reaction, inflammation around each cysticercus eventually develops, accompanied by edema, reactive gliosis, and formation of dense exudates in the subarachnoid space composed of collagen, lymphocytes, multinucleated giant cells, eosinophils, and hyalinized parasitic membranes. In the spine this causes myeloradiculitis with entrapment of nerve roots and blood vessels. Clinical manifestations. Cysticercosis is a pleomorphic disease but diagnostic criteria have been clearly established (Del Brutto et al., 1996, 1998, 2001). Involvement of the spinal cord is a very rare form of cysticercosis and intramedullary cysts are even less common. Patients may present with a clinical syndrome of cerebral neurocysticercosis associated with both cauda equina and Brown-Se´quard syndromes and CSF findings of eosinophilic meningitis (Torabi et al., 2004). Imaging. Leite et al. (1997) reviewed the imaging experience in 16 patients with spinal cord involvement demonstrated by surgery or laboratory tests in four medical

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centers (two in the US, one each in Brazil and Colombia). On MRI imaging isolated intradural-extramedullary involvement was seen in nine patients; isolated intramedullary involvement (n ¼ 3), combined intraduralextramedullary and intramedullary involvement (n ¼ 3), and syringomyelia caused by infection and associated with chronic spinal arachnoiditis (n ¼ 2). Lesions included cystic structures within the subarachnoid space (Fig. 102.11) or homogeneous sheet-like enhancement within the subarachnoid space (arachnoiditis) over the surface of the spinal cord. Evidence of intramedullary disease included focal cystic lesions or syringomyelia due to cavitation of the spinal cord. All patients had evidence of simultaneous intracranial cysticercosis as shown on cranial CT, MR imaging, or both. Imaging of parenchymal cerebral cysticercosis usually shows single or multiple cysts with the typical “hole-in-donut” appearance resulting from imaging of the scolex of the parasite. Characteristic findings of subarachnoid lesions include abnormal enhancement of the leptomeninges and cystic lesions. Multiple calcified lesions (“starry sky”) on CT are seen in cases with spontaneous resolution. Laboratory. CSF usually shows lymphocytic pleocytosis (up to 500 cells per mm3) often with increase of eosinophils (eosinophilic meningitis), increased protein (up to 2000 mg/dL), and normal glucose. Useful serologic tests are serum immunoblot and CSF-ELISA. Treatment. Therapy must be individualized according to the location of parasites and the degree of disease activity. Albendazole (15 mg/kg/day) for 8 days is advised for patients with viable subarachnoid or parenchymal cysts. Dexamethasone (16 mg/day) administration should begin prior to the start of albendazole therapy and should be prolonged for several days. According to Del Brutto and colleagues (2006), both albendazole and praziquantel, the two cysticidal drugs available for neurocysticercosis, are effective in achieving complete resolution of colloidal and vesicular cysticerci with a reduction of up to 67% in the frequency of seizures. For patients with hydrocephalus, shunt placement must be contemplated before the start of albendazole. There is no systematic analysis of results of treatment of spinal forms of cysticercosis.

MYELITIS PRESENTING WITH EOSINOPHILIC MENINGITIS In addition to bilharziasis and cysticercosis, other parasitic diseases may present with eosinophilic pleocytosis in the CSF or eosinophilic meningitis. The presence of eosinophils in the CSF can only be demonstrated with Giemsa or Wright stain and CSF eosinophilia is defined by more than 10 eosinophils per mL or more than 10% of the total CSF leukocyte count (Graeff-Teixeira

G.C. ROMA´N

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Fig. 102.11. Spinal neurocysticercosis. Contrast-enhanced MRI of spine showing a well-defined intramedullary cystic lesion expanding the cord opposite D8 vertebral body, which is hypointense on T1 (saggital cuts (A), axial cuts (D)) and hyperintense on T2 (B). The cyst had two areas of altered signal inside, which were hyperintense on T1 and isointense on T2, representing scoleces. The cyst showed peripheral enhancement and perifocal edema (C). Follow-up MRI of the spine 2 months later showed no cysticercus (E). (Reproduced from Ahmad and Sharma, 2007.)

et al., 2009). Helminthic infections of the nervous system are the most common cause of CSF eosinophilia. Although benign aseptic meningitis is the most common clinical picture of eosinophilic meningitis caused by Angiostrongylus cantonensis, other, highly mobile and larger parasites such as Gnathostoma spinigerum and Baylisascaris procyonis usually cause meningoencephalitis and myelitis. Table 102.4 summarizes the geographic distribution of the most common causes of eosinophilic meningitis, including angiostrongyliasis, gnathostomiasis, schistosomiasis, toxocariasis, baylisascariasis, cysticercosis, paragonimiasis, and less frequently Table 102.4 Geographic distribution of nematode larvae causing eosinophilic meningitis and myelitis Geographic distribution Gnathostoma spinigerum Angiostrongylus cantonensis Angiostrongylus costaricensis Toxocara canis Baylisascaris procyonis

Southeast Asia Southeast Asia Central America Worldwide North America

(Reproduced from Schmutzhard, 2007, with permission from BMJ Publishing Group Ltd. Copyright © 2007.)

strongyloidiasis, trichinellosis, hydatidosis, coenurosis, and filariasis. Rarely, fungal infections (coccidioidomycosis), syphilis, lymphoma, illicit drugs, and CSF shunts may cause eosinophilic pleocytosis.

GNATHOSTOMIASIS Human infection by the nematode Gnathostoma spinigerum results from eating raw fish, snails, shrimp, snakes, frogs, or insufficiently cooked chicken or duck contaminated with larvae of this parasite. Once ingested, the highly motile larvae cross the intestinal wall and migrate to subcutaneous tissues, skeletal muscle, and internal organs, including the CNS. Dogs, cats, and pigs are definitive hosts (Fig. 102.12). Gnathostomiasis is endemic in tropical areas of Southeast Asia, particularly in Thailand, as well as in Central and South America. CNS involvement is rather common in Asia and rare in the Americas. Gnathostomiasis has been associated with transverse myelitis, meningitis, and subarachnoid or parenchymal brain hemorrhages. Intracranial hemorrhages occur in 15–30% of patients with cerebral involvement, and are the most severe complication of the disease. Autopsy shows that Gnathostoma larvae may form long hemorrhagic tracts extending from the basal ganglia to the lower brainstem. Neurologic forms of presentation

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Fig. 102.12. Sagittal MRI of spinal cord, T1-weighted images after intravenous gadolinium contrast demonstrating abnormal signal intensities at upper and lower thoracic levels (circled) in a patient with eosinophilic meningomyelitis from larvae migrans of the cat nematode Gnathostoma spinigerum. (Reproduced from Schmutzhard, 2007.)

include transverse myelitis, seizures, meningitis, subarachnoid hemorrhage, and focal neurologic deficits associated with parenchymal brain hemorrhages. In contrast with angiostrongyliasis, the CSF is usually bloody and xanthochromic, with eosinophilic pleocytosis (up to 3000 cells/mm3), mild increase in protein, and normal glucose. High blood eosinophilia is present. Neuroimaging may show unusually long or multiple parenchymal brain hemorrhages or evidence of multiple foci of myelitis. Diagnosis is confirmed by identification of the larvae in tissue samples. Nematode-specific serologic diagnostic tests are not commercially available. Eosinophilic meningomyelitis should be treated with a combination of antihelminthics and intravenous corticosteroids. Schmutzhard (2007) successfully used albendazole (400 mg twice per day for 4 weeks) in combination with intravenous dexamethasone (24 mg/ day, slowly tapering off) and obtained complete cure of a patient with myelitis from gnathostomiasis.

TOXOCARIASIS Ascaris lumbricoides is a common intestinal parasite of humans with worldwide distribution. The equivalent ascarids of cats and dogs are Toxocara catis and Toxocara canis, which cause visceral larva migrans in humans, but only T. canis is capable of invading the CNS. According to Vidal and colleagues (2003), the

clinical syndromes include ocular forms, eosinophilic meningitis (36%), myelitis (28%), and encephalitis (62%). CSF eosinophilic pleocytosis occurs in at least 74% of patients, along with modest elevation of proteins and normal or slightly reduced glucose. Elevation of eosinophils in peripheral blood is constant. MRI of the spine shows enhancing lesions; similar hyperintense micronodular lesions are present in the brain on T2-weighted MRI images; parenchymal or intraventricular hemorrhage may also occur. The usual treatment is albendazole (5 mg/kg to 15 mg/kg twice a day for 2–4 weeks) plus intravenous corticoids to control potential vasculitis.

BAYLISASCARIASIS Human infection with the large ascarid worm Baylisascaris procyonis, which infects raccoons (Procyon lotor), a native North American animal, cause a severe visceral larva migrans syndrome. Once ingested, the larvae migrate out of the intestine causing first cutaneous larva migrans with macular rash on the face and trunk, followed by ocular disease and concomitant neurologic disease manifested by an acute, severe, and rapidly progressive eosinophilic meningoencephalitis or meningomyelitis that is usually fatal if untreated. Antibodies can be detected in serum and CSF. MRI shows extensive enhancing white matter lesions. Surviving cases have been

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treated with albendazole (20 mg/kg/day to 40 mg/kg/day for 1–4 weeks) in addition to intravenous corticosteroids. Prophylactic treatment for at least 10 days with albendazole (20 mg/kg/day to 40 mg/kg/day) or thiabendazole (50 mg/kg/day) is recommended immediately after exposure to raccoon latrines or cages.

IMMUNE-INFLAMMATORY DISORDERS Acute transverse myelitis This is a rare disorder with an incidence of 1–8 new cases per million of population per year; 20% of all cases occur in patients younger than 18 years of age (Bigi et al., 2010). Acute transverse myelitis is the most common cause of spinal cord transection evolving over a period of hours or days, usually with minimal back pain. The diagnosis remains one of exclusion; as mentioned earlier, nucleus pulposus embolism must be considered in the differential diagnosis. Treatment with corticosteroids is recommended given that 20–40% of patients with acute transverse myelitis have evidence of preceding or concurrent viral infection, and that the myelitis is the result of a postinfectious demyelination rather than an acute infectious myelitis (Berger and Sabet, 2002). This condition often occurs after a viral infection or vaccination particularly after rabies vaccination and posthepatitis B vaccination. Also, human rabies may present as a viral transverse myelitis, usually following bat bites. Konzo, a form of acute-onset spastic paraplegia occurring in African children who survive on a diet of cassava, appears to be due to the combination of excessive cyanide consumption and poor dietary intake of sulphurcontaining amino acids (Tylleska¨r et al., 1992; Rosling and Tylleska¨r, 1996). Lyme borreliosis may present rarely as acute transverse myelitis (Bigi et al., 2010). In Taiwan, Lyme neuroborreliosis is often manifested as an acute myelopolyradiculitis, a feature that is different from Lyme disease in Europe and North America (Chang et al., 2010). Neurosyphilis can rarely present as acute transverse myelitis (Lowenstein et al., 1987).

Multiple sclerosis Multiple sclerosis is considered a rare disease in the tropics probably because sunlight exposure and increased synthesis of vitamin D have protective immunomodulatory effects against autoimmune diseases. Conditions such as systemic lupus erythematosus and Sj€ogren disease are exceptional in the tropics, except for cases associated with HTLV-1 infection. Kompoliti et al. (1996) and Nakamura et al. (2000) described cases of Sj€ ogren syndrome with HTLV-1 myelitis. A number of well-documented cases of multiple sclerosis have been reported from Africa and

Latin America. In cases from Colombia, a genetic association was found for the allele 202 belonging to the marker D6S276 and for the allele 114 belonging to the marker D6S265 at different loci, establishing an association among polymorphisms of genes located at 6p21.3-21.4 correlated with the TNF neighborhood (Palacio et al., 2002). Devic’s disease (neuromyelitis optica), characterized by the simultaneous occurrence of bilateral optic neuritis and transverse myelitis, was considered a form of multiple sclerosis observed more commonly in Asia (India, Japan) and the Caribbean. However, with the discovery that most cases of Devic’s disease are associated with serum anti-aquaporin-4 antibodies (NMO-IgG) this condition is now considered to be an autoimmune, antibodymediated disease directed against the main brain water channel, aquaporin-4 (AQP4).

NUTRITIONAL MYELONEUROPATHIES Recently, Gallo Diop et al. (2006) have revised for the World Health Organization the neurologic disorders associated with malnutrition. The prototypic nutritional myeloneuropathy is subacute combined degeneration due to cobalamin (vitamin B12) deficiency and will be reviewed here more extensively. Neurologic signs occur relatively late in situations of dietary restriction or when absorption of nutrients is impaired, such as in tropical malabsorption or following bariatric surgery. When the deficiency of essential nutrients is severe enough to injure the nervous system or when protective nutrients – such as sulfur-containing amino acids and antioxidant carotenoids such as lycopene – become unavailable the neuronal groups most sensitive to energy deficiency (dorsal root ganglia, large myelinated distal axons, bipolar retinal neurons, cochlear neurons) are the first to suffer damage and manifest symptoms earliest. Nutritional neuropathies may occur as epidemic outbreaks or as problems endemic to a particular geographic area. Although experimentally, selective deficiency of micronutrients, in particular B-group vitamins and vitamin E, have been associated with axonal neuropathies, in tropical regions specific vitamin deficits seldom occur, since most instances of human malnutrition are usually due to overall dietary deficiency. Tropical malabsorption, resulting from recurrent infections with toxicogenic E. coli and other bacteria, viral gastroenteritis, and intestinal parasites, plays a significant role by decreasing the availability of vitamins. Precipitating factors include pregnancy and lactation, infections such as malaria and diarrhea, as well as increased metabolic requirements for thiamine due to increased carbohydrate intake and intense physical activity under hot and humid weather conditions.

TROPICAL MYELOPATHIES A toxic-nutritional etiology often combines deficiencies of micronutrients with consumption of neurotoxins such as cyanide-producing tropical foodstuffs (cassava), alcohol abuse and tobacco smoking (alcohol-tobacco amblyopia).

Vitamin B12 (cobalamin) Myelopathy, peripheral neuropathy and optic neuropathy were recognized as common neurologic complications of pernicious anemia. History. In 1926, George Minot and William Murphy discovered that dietary consumption of liver was beneficial in pernicious anemia causing improvement of sensation in patients with spinal cord involvement. In 1929, Castle postulated that extrinsic and intrinsic factors were required to absorb the antipernicious anemia factor present in liver tissue. Vitamin B12 was eventually crystallized in 1948 and its coenzyme forms purified from liver extracts. In 1956, Dorothy Hodgkin elucidated the complex, three-dimensional structure of vitamin B12. Cobalamin. The coenzyme form is cobalamin, a complex organometallic corrin ring with a cobalt (Coþ) in the central position, similar to the one occupied by iron in the heme ring. Vitamin B12 is available as cyanocobalamin. Neither animals nor plants produce vitamin B12 and only microorganisms are capable of synthesizing this vitamin. Humans are totally dependent on the vitamin B12 available in animal tissues to fulfill the daily requirements (2–3 mg/day). Strict vegan and macrobiotic diets do not provide this essential nutrient and may result in increased homocysteine, macrocytic anemia, or signs of neurologic involvement. Vitamin B12 absorption. Cobalamin absorption is quite complex and involves at least five separate cobalamin-binding molecules, receptors and transporters. The process includes a salivary factor, release of cobalamin from dietary sources by peptic and acid digestion in the stomach; binding to haptocorrin in the stomach and then to the intrinsic factor (IF) produced by gastric parietal cells. The IF-cobalamin complex passes into distal ileum, where it binds to high-affinity IF receptors on ileal epithelial cells, to be absorbed in the distal small intestine. Cobalamin is then released for subsequent binding to transcobalaminII (TcII). The TcII-cobalamin complex is transported across the cell to be released into the circulation. All cells in the body have surface receptors for TcII-cobalamin complex. However, 90% of the cobalamin in plasma is protein-bound to transcobalamin-I and transcobalaminIII, probably as storage forms. Vitamin B12 deficiency. Cobalamin deficiency occurs from a large number of factors including absent dietary supply (vegans), antibodies against IF (pernicious

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anemia), gastrectomy, gastritis involving parietal cells in gastric fundus (Helicobacter pylori), malabsorption syndromes (tropical sprue), celiac disease, surgical resection or bypass of distal ileum, competition for vitamin B12 by bacterial proliferation in the intestine in the blind-loop syndrome, or by intestinal parasitism with the fish tapeworm Diphyllobotrium latum, and rare genetic enzyme deficiencies (methylmalonic aciduria). Inhalation of nitrous oxide in anesthesia or as a recreational drug produces cobalamin deficiency. The elderly are prone to vitamin B12 deficiency; about 10–15% of the elderly have cobalamin levels below 150 pmol/L, and almost half have serum elevations of sensitive markers such as homocysteine or methylmalonic acid (Wolters et al., 2004). Atrophic gastritis occurs in 20–50% of the elderly (Andre`s et al., 2004, 2008) and results in gastric achlorhydria and low pepsinogen secretion that prevent the release and absorption of cobalamin; alkalinization of the small intestine and bacterial overgrowth further decreases the bioavailability of cobalamin. Drugs such as metformin for diabetes, and use of antacids such as proton pump inhibitors or H2 receptor antagonists inhibit cobalamin absorption. Epidemiology. Pernicious anemia is common throughout the world, especially in persons of European or African descent (Rogers et al., 2003; Stabler and Allen, 2004). Dietary deficiency of vitamin B12 due to vegetarianism is increasing, particularly in Asia, North America, and Europe, causing hyperhomocysteinemia that raises the risk for vascular disease. Breast-fed infants of vitamin B12-deficient vegan mothers are at risk for severe developmental abnormalities, growth failure, anemia, lower academic performance, attentional deficits, and delinquent behavior. Dietary vitamin B12 deficiency is a severe problem on the Indian subcontinent, in Mexico, Central and South America, and in some African countries (Black, 2003; Stabler and Allen, 2004). Pathogenesis. Cobalamin-dependent enzymes catalyze two types of reactions: rearrangements such as the conversion of L-methylmalonyl coenzyme A (CoA) to succinyl CoA; and methylations, as in the synthesis of methionine. Deficiency of either vitamin B12 or folate inhibits purine and thymidylate syntheses, impairs DNA production, causes erythroblast apoptosis in hematopoietic tissues and leads to the megaloblastic anemia typical of pernicious anemia. Methionine is also important in the synthesis of S-adenosylmethionine (SAM), the major donor of methyl groups. The provision of activated methyl groups by SAM is the end result of the activated methyl cycle, important in the synthesis of norepinephrine and glutamate, as well as in myelin synthesis. Neurologic manifestations of vitamin B12 deficiency. Some effects of vitamin B12 deficiency appear to be

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oxidative in nature, partly mediated by increased homocysteine, as well as by abnormal production of cytokines (tumor necrosis factor-a, interleukin-6) and deficit of epidermal growth factor, a neurotrophic factor (Scalabrino et al., 2003). Signs of neurologic involvement in vitamin B12 deficiency may occur before the development of megaloblastic anemia; and rarely, with normal serum levels of vitamin B12 (Healton et al., 1991). A more sensitive indicator of neural damage is the presence of increased homocysteine, methlymalonic acid (MMA) and methyl-citric acid (Garcia et al., 2004). The spinal cord, brain, optic nerves, and peripheral nerves may be affected by vitamin B12 deficiency. Subacute combined degeneration. The typical lesion of the spinal cord in vitamin B12 deficiency is the degeneration of posterior and lateral columns causing subacute combined degeneration (SCD) manifested by a triad of sensory ataxia, spasticity and leg weakness (Healton et al., 1991). Symptoms begin with paresthesias, tingling, pins and needles sensations in the feet and then in the hands; Lhermitte’s sign may be present. These symptoms are constant and progress towards unsteadiness of gait due to pyramidal weakness and loss of proprioception and postural sense, with a positive Romberg sign caused by both damage to the posterior funiculi and the peripheral neuropathy. As the disease progresses, stiffness and weakness of the legs develop, with brisk knee reflexes, crossed adductor responses and Babinski sign. In a large series of patients with pernicious anemia, common symptoms included loss of cutaneous sensation, weakness, urinary or fecal incontinence, and orthostatic hypotension. About one in four patients had no evidence of anemia. The final stage in untreated cases is an ataxic paraplegia, with spasticity and contractures; flaccid paraplegia may occur in some patients, probably due to more severe peripheral nerve involvement. Response to treatment was inversely related to duration and severity of the neurologic symptoms and the anemia before the diagnosis. Neuropathology. The typical pathology involves the white matter in the spinal cord beginning with separation of myelin lamellae, vacuolization, and axonal damage with minimal gliosis, involving first the dorsal columns of the cervical and upper thoracic cord. Late lesions are scattered irregularly in posterior and lateral funiculi and disclose a typical honeycomb appearance. Visual symptoms due to involvement of the optic nerves were commonly seen in pernicious anemia. Clinically, there is loss of visual acuity and color vision and cecocentral scotomata, similar to those of other nutritional optic neuropathies. At autopsy, spongy degeneration of the optic nerves is usually found. In a model of dietary vitamin B12 deficiency in monkeys, neuropathologic examination revealed loss of ganglion

cells in the macula with early involvement of the maculopapillary bundles, extending to the retrobulbar portion of the optic nerves. CNS changes in the monkeys occurred after 33–45 months of deficiency, similar to the time required to produce vitamin B12 deficiency in humans. Sensory peripheral neuropathy also occurs in vitamin B12 deficiency, with a typical stocking-and-glove distribution, with loss of vibratory perception increasing the sensory symptoms due to dorsal column involvement. Unusual forms of presentation of vitamin B12 deficiency include cranial neuropathies with hoarseness from vocal cord paralysis, disturbances of taste and smell, tinnitus; nocturnal tabetic-type pains, upward or lateral gaze limitation, cerebellar dysfunction, and movement disorders occur in addition to the typical myelopathic manifestations. Cognitive and neuropsychiatric symptoms are frequently observed in patients with myelopathy from pernicious anemia; in some patients these were the presenting features (Garcia et al., 2004; Garcia and Zanibbi, 2004; Vogel et al., 2009). Diagnosis. The diagnosis of vitamin B12 deficiency from pernicious anemia is usually made in the presence of positive anti-IF antibodies, low levels of vitamin B12, and increased levels of homocysteine and MAM. Macrocytic anemia and neutrophil polysegmentation need not be present. Treatment. Neurologic complications of vitamin B12 deficiency are treated with intramuscular injections of 1000 mg of vitamin B12 daily for 5 days to replenish the stores, followed by monthly injections of 500–1000 mg indefinitely. Nasal spray and sublingual vitamin B12 are available. For preventive treatment, oral preparations of vitamin B12 appear to be adequate.

Toxic-nutritional myelopathies Two geographically well-defined conditions will be described: tropical ataxic myeloneuropathy in Nigeria and epidemic neuropathy in Cuba.

TROPICAL ATAXIC MYELONEUROPATHY This condition, also known as endemic ataxic polyneuropathy or tropical ataxic neuropathy (TAN) was first observed in an endemic area in southwestern Nigeria, in places where the diet depends almost exclusively on cassava (Osuntokun, 1968; Oluwole et al., 2000). In the 1960s, this toxic-nutritional myeloneuropathy used to reach estimated prevalences as high as 18–26 per 1000, with equal sex distribution. Onset was usually in the third and fourth decades. The chronic and slowly progressive syndrome is characterized by predominantly sensory polyneuropathy, posterior column involvement,

TROPICAL MYELOPATHIES optic atrophy, and sensorineural deafness. Symptoms include painful paresthesias in the legs, numbness, “burning feet,” and cramps. On examination there is impaired vibratory perception distally in the feet, and loss of knee and ankle reflexes. Two-thirds of the patients have incoordination of the legs and broad-based ataxic gait. Weakness and atrophy of distal leg muscles, mainly the peroneal-soleus muscles, may also occur. Other symptoms include blurring of vision with eventual bilateral optic atrophy (81%), and tinnitus followed by bilateral nerve deafness (36%). A few patients have pyramidal signs. About 40% of patients present skin and mucosal lesions suggestive of vitamin deficits. In other African countries such as Senegal, similar syndromes have been observed in malnourished populations, although not necessarily in association with high cassava intake. The frequency of visual loss (19%), deafness (13%), and mucocutaneous lesions (15%) is much lower in these patients than in those from Nigeria. Oluwole and colleagues (2000, 2002, 2003) conducted extensive studies on the role of chronic cyanide ingestion in ataxic neuropathy in Nigeria. Exposure to cyanide from cassava foods was proposed as the major causal factor. However, occurrence of ataxic polyneuropathy is rare in many parts of the tropics where cassava foods are the major source of calories. Consumption of cassava foods and exposure to cyanide from cassava foods were compared in the endemic and nonendemic areas. Efficiencies of the methods of processing cassava roots to gari and lafun, two common cassava foods in Nigeria, were compared, and changes in the level of cyanogenic compounds in gari during storage were studied. No association of occurrence of ataxic polyneuropathy and exposure to cyanide from cassava foods was demonstrated. In Nigeria, exposure to cyanide from cassava foods varies widely due largely to differences in the frequency of intake of cassava foods and the amount of cyanogenic compounds in cassava foods resulting from the method of processing cassava roots, the duration of storage of cassava, and the method of preparation of the meals. A reduction of exposure to cyanide from cassava foods was recommended. Other clinical syndromes associated with malnutrition and chronic cyanide intoxication included konzo, nerve deafness and tropical (nutritional) amblyopia. The latter is probably clinically identical to the retrobulbar neuropathy of pernicious anemia due to vitamin B12 deficiency. The common element in all the above conditions is the underlying deficit of micronutrients, in particular B-group vitamins, folic acid, and sulfur amino acids. Differential diagnosis should include methyl alcohol intoxication, a common cause of epidemic blindness in the tropics resulting from consumption of adulterated alcohol.

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Konzo This is the traditional name given in Kwango, Congo, to a form of epidemic spastic paraparesis described during times of drought and famine in cassava-staple areas (Rosling, 1986; Tylleska¨r et al., 1992; Tylleska¨r, 1994; Rosling and Tylleska¨r, 1996). Epidemics have occurred in rural areas of Mozambique, Tanzania, Zaire (Congo), and the Central African Republic. The disease predominates in children (63%) and lactating women, with prevalences ranging from 29 to 34 per 1000. Women and children eat raw and sun-dried, uncooked bitter cassava, whereas men normally eat well-cooked cassava. Traditional methods of cassava preparation in Africa such as soaking, fermentation and sun-drying leave substantial amounts of cyanogenic glycosides in the cassava meal. Signs of acute cyanide intoxication are present, followed by a clinical picture characterized by sudden onset of nonprogressive spastic paraparesis with flexion contractures of hamstrings and Achilles tendons developing later. Scissoring gait and toe walking are frequently present and patients require one or two sticks to walk. Increased tone in the lower limbs, hyperreflexia, ankle clonus, and Babinski signs are usually present. There is no sensory loss to light touch or pinprick. Impairment of rapid movements and hyperreflexia in the upper limbs are also present. About half the patients have optic neuropathy with decreased visual acuity, visual fields deficits with cecocentral scotomata and pallor of the temporal optic disc. Abnormal visual evoked potentials also occur. Pendular nystagmus and dysarthria may be found. There is minimal recovery with a nutritious diet and vitamin therapy.

CUBAN EPIDEMIC MYELONEUROPATHY A cluster of nutritional myeloneuropathies was observed in Cuba in 1993 (Roma´n, 1994). Epidemiology. This epidemic neuropathy affected 50 862 patients during 1991–1994 (CDC, 1994) with an incidence rate of 462 cases per 100 000. Most cases occurred between ages 25 and 64 years while children, adolescents, pregnant women and the elderly were rarely affected. The highest rates were found in the tobaccogrowing province of Pinar del Rı´o. Patients were farmers, with lower income and less education than healthy controls. Clinical manifestations. Clinical manifestations included retrobulbar optic neuropathy, sensorineural deafness, predominantly sensory and autonomic neuropathy, and dorsolateral myelopathy. Less often dysphonia, dysphagia, and spastic paraparesis were present. Mixed forms were frequent. Neurologic

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symptoms were preceded by weight loss, anorexia, chronic fatigue, lack of energy, irritability, sleep disturbances, and difficulties with concentration and memory. The most common form of spinal cord involvement was a dorsolateral myelopathy presenting with sensory symptoms along with complaints of leg weakness, increased urinary frequency, impotence in males, and difficulty walking. These cases often had brisk knee reflexes with crossed adductor responses contrasting with decreased ankle reflexes. Spasticity and Babinski signs were usually absent. Proximal motor weakness was present in one-third of these cases. Significant decrease in position sense in the feet, and a positive Romberg sign, were often present. Severe cases had sensory gait ataxia. The majority of cases had optic neuropathy characterized by blurred vision, photophobia, central and cecocentral scotomata, deficit of color vision for red and green, and loss of axons in the maculopapillary bundle with temporal disc pallor in advanced cases. One-third of the patients presented concomitant skin and mucous membrane lesions, evidence of peripheral nerve and spinal cord involvement and 20% had hearing loss. Symptoms of peripheral neuropathy included painful dysesthesias in soles and palms, mainly burning feet, numbness, cramps, and paresthesias. Nerves were sensitive to pressure. Motor involvement was minimal. Objective signs were often mild and included loss or decreased perception of vibration, light touch, and pinprick distally in the limbs in a stocking-glove pattern. Achilles tendon reflexes were decreased or absent. Motor nerve conduction velocities were normal and sensory nerve potential amplitudes were decreased only in severe cases. Some patients presented a sensation of body heat with excessive sweating, as well as coldness and hyperhidrosis of hands and feet. Sural nerve biopsies showed an axonal neuropathy with predominant loss of myelinated large caliber fibers (Borrajero et al., 1994). Patients with sensorineural deafness complained of high-pitch tinnitus and deafness. Pure tone audiometry demonstrated high frequency (4–8 kHz) hearing loss, bilateral and usually symmetrical. There were no associated vestibular symptoms. Etiology. Possible etiologies excluded were toxic (organophosphorus pesticides, chronic cyanide, trichloroethylene), genetic such as mitochondrial mutations of Leber’s hereditary optic neuropathy (Newman et al., 1994), and infectious causes (retroviruses such as HIV and HTLV-1/2, Coxsackie viruses). According to the Cuba Neuropathy Field Investigation Team (1995), factors associated with greater risk of optic neuropathy were the following: use of tobacco, in particular cigar smoking – those who smoked  4 cigars per day had the highest risk, lack of food for several days, eating lunch < 5 days per week, and eating breakfast < 1/week.

Protective factors included having relatives overseas (probably because with US dollars it was possible to buy supplementary food in the black market) and raising chickens at home (perhaps because of the nutritional value of eggs in terms of B-group vitamins and sulfurcontaining amino acids). High levels of lycopene (a nonvitamin A carotenoid antioxidant found in tomatoes, guavas, watermelons, and other red fruits) provided the strongest association with protection. Consumption of riboflavin, an antioxidant, was also protective. In summary, the etiology was basically nutritional with an added toxic component from tobacco use. Treatment and prevention. Marked improvement of vision was obtained with parenteral B-group vitamins and folic acid. Therefore, despite the absence of overt malnutrition in Cuba, a deficit of B-group vitamins, mainly cobalamin and thiamine, compounded by lack of essential sulfur-amino acids in the diet, was the cause of the outbreak. Cuba had eliminated childhood malnutrition and nutritional supplementation programs for children, pregnant women, and the elderly were maintained despite enormous difficulties resulting from political reasons. This explains the absence of cases in these groups so often affected by nutritional neuromyelopathies in the tropics.

TOXIC MYELONEUROPATHIES Cyanide A number of staple foods in the tropics contain large amounts of cyanogenic glycosides. These plants include cassava (Manihot esculenta, Crantz; yuca Spa., manioc Fr.), yam, sweet potato, corn, millet (Sorghum sp.), bamboo shoots, and beans such as Phaseolus vulgaris, particularly lima beans and the small black lima beans which grow wild in Puerto Rico and Central America. Tobacco smoke (Nicotiana tabacum) also contains considerable amounts of cyanide (150–300 mg per cigarette). Hydrolysis of plant glycosides releases cyanide as hydrocyanic acid. Intoxication occurs by rapid cyanide absorption through the gastrointestinal tract or the lungs. Detoxification is mainly to thiocyanate in a reaction mediated by a sulfur-transferase (rhodanase), which converts thiosulphate into thiocyanate (SCN) and sulfite. Thiocyanate is a goitrogenic agent that may be responsible for endemic cretinism in some tropical areas. The sulfur-containing essential amino acids (cystine, cysteine, and methionine) provide the sulfur for these detoxification reactions. Also important is vitamin B12 with conversion of hydroxocobalamin to cyanocobalamin. Cassava is a root-crop consumed in large quantities throughout the tropics and constitutes the major source of calories for some 300 million people. In Africa, cassava is the staple diet in western Nigeria, Congo, Tanzania, Senegal, Uganda, and Mozambique. In these

TROPICAL MYELOPATHIES countries, a number of neurologic disorders have been associated with high dietary intake of cyanogenic glycosides in association with depletion of sulfur-containing amino acids. However, it should be noted that these problems are not common in Latin America, even though the cassava consumption in countries such as Brazil is among the highest in the world.

Lathyrism Bruyn and Poser (2000) have extensively reviewed the history of lathyrism. Known since classic times, lathyrism is the cause of epidemic outbreaks of spastic paraparesis in the tropics. Lathyrism is caused by excessive dietary consumption of peas of the Lathyrus family, especially L. sativus (chickling pea). Lathyrism is still endemic in regions of India, Bangladesh, and Ethiopia and continues to be a public health problem (Ludolph et al., 1987). Previous outbreaks were described in Europe, North Africa, and parts of Asia, mainly in times of war, famine, or drought. The cause is b-N-oxalylamino-L-alanine (BOAA), a neurotoxic amino acid, considered the neurotoxin responsible for the spastic paraparesis of human lathyrism (Spencer et al., 1987). Lathyrism begins after weeks or months of consumption of the peas and usually occurs in a setting of protein-calorie malnutrition. Onset is acute, subacute, or insidious. Cramps in the calf muscles are an early sign followed by increased muscle tone, spasticity, brisk reflexes, and Babinski sign. Sensory loss is typically absent, although by clinical neurophysiology, slight damage to the dorsal columns is also present. The marked spasticity and hypertonia of the thigh extensor and adductor muscles and in the gastrocnemius muscles result in a typical gait on the balls of the feet with a lurching scissoring gait. Eventually there is permanent slight flexion of hips and knees, retraction of Achilles tendons, adductor crossing, and feet in plantar flexion; paraplegia in flexion is the eventual outcome. Neuropathological examination reveals obvious fiber loss in the pyramidal tracts, mainly in the lumbar cord, along with pallor of the fasciculi gracilis and axonal swelling in Goll’s nuclei. Lathyrism is irreversible and there is no specific treatment.

Fluorosis Endemic fluorosis is a condition described initially in some areas of India with high concentrations of fluorine in drinking water (Singh et al., 1963). The condition is characterized by excessive ossification of bones causing compressive myelopathy of the cervical cord and radicular compression. Surgical decompression is indicated (Misra et al., 1988). Public health measures have been implemented to prevent fluorosis.

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REFERENCES Afzelius A (1921). Erythema chronicum migrans. Acta Derm Venereol 2: 120–125. Ahmad FU, Sharma BS (2007). Treatment of intramedullary spinal cysticercosis: report of 2 cases and review of literature. Surg Neurol 67: 74–77. Andre`s E, Loukili NH, Noel E et al. (2004). Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 171: 251–259. Andre`s E, Vogel T, Federici L et al. (2008). Cobalamin deficiency in elderly patients: a personal view. Curr Gerontol Geriatr Res 2008: 848267. Bale´riaux DL, Neugroschl C (2004). Spinal and spinal cord infection. Eur Radiol 14: E72–E83. Bannwarth A (1941). Chronische lymphocyta¨re Meningitis, entz€ undliche Polyneuritis und “Rheumatismus”. Ein Beitrag zum Problem “Allergie und Nervensystgem”. Arch Psychiatr Nervenkr 113: 284–376. Batra S, Arora S, Meshram H et al. (2011). A rare etiology of cauda equina syndrome. J Infect Dev Ctries 5: 79–82. Berger JR, Sabet A (2002). Infectious myelopathies. Semin Neurol 22: 133–141. Bigi S, Aebi C, Nauer C et al. (2010). Acute transverse myelitis in Lyme neuroborreliosis. Infection 38: 413–416. Black MM (2003). Micronutrient deficiencies and cognitive functioning. J Nutr 133: 3927S–3931S. Borrajero I, Pe´rez JL, Domı´nguez C et al. (1994). Epidemic neuropathy in Cuba: morphological characterization of peripheral nerve lesions in sural nerve biopsies. J Neurol Sci 127: 68–76. Bouattour A, Ghorbel A, Chabchoub A et al. (2004). Lyme borreliosis situation in North Africa. Arch Inst Pasteur Tunis 81: 13–20. Bruyn GW, Poser CM (2000). The History of Tropical Neurology: Nutritional Disorders. Science History Publications, Canton, MA. Burgdorfer W (1998). Lyme disease – a tick-borne spirochetosis? Science 216: 1317–1319. Burgdorfer W, Barbour AG, Hayes SF et al. (1983). Erythema chronicum migrans – a tickborne spirochetosis. Acta Trop 40: 79–83. Castillo LC, Gracia F, Roma´n G et al. (2000). Spino-cerebellar syndrome in patients with HTLV-I/II infection. Acta Neurol Scand 101: 405–412. CDC: Centers for Disease Control and Prevention (1994). Epidemic neuropathy – Cuba, 1991–1994. MMWR 43: 183–192. Chang B-L, Shih C-M, Ro L-S et al. (2010). Acute neuroborreliosis with involvement of the central nervous system. J Neurol Sci 295: 10–15. Corbel MJ (1997). Brucellosis: an overview. Emerg Infect Dis 3: 213–221. Cuba Neuropathy Field Investigation Team (1995). Epidemic optic neuropathy in Cuba – clinical characterization and risk factors. N Engl J Med 333: 1176–1182. De Backer AI, Mortele´ KJ, Vanschoubroeck IJ et al. (2005). Tuberculosis of the spine: CT and MRI imaging features. Journal Belge de Radiologie – Belgisch Tijdscrift voor Radiologie JBR-BTR 88: 92–97.

1546

G.C. ROMA´N

Del Brutto OH, Wadia NH, Dumas M et al. (1996). Proposal of diagnostic criteria for human cysticercosis and neurocysticercosis. J Neurol Sci 142: 1–6. Del Brutto OH, Sotelo J, Roma´n G (1998). Neurocysticercosis: A Clinical Handbook. Swets and Zeitlinger. Del Brutto OH, Rajshekhar V, White AC et al. (2001). Proposed diagnostic criteria for neurocysticercosis. Neurology 57: 177–183. Del Brutto OH, Carod-Artal FJ, Roma´n GC et al. (2002). Tropical neurology. Continuum, Lifelong Learning Neurol 8: 36–49. Del Brutto OH, Roos KL, Coffey CS et al. (2006). Metaanalysis: cysticidal drugs for neurocysticercosis: albendazole and praziquantel. Ann Intern Med 145: 43–51. Devinsky O, Cho E-S, Petito CK et al. (1991). Herpes zoster myelitis. Brain 114: 1181–1196. Estanislao LB, Pachner AR (1999). Spirochetal infection of the nervous system. Neurol Clin 17: 783–800. Ferrari TCA, Moreira PRR, Cunha AS (2008). Clinical characterization of neuroschistosomiasis due to Schistosoma mansoni and its treatment. Acta Trop 108: 89–97. Fisher M, Poser CM (1977). Syphilitic meningomyelitis. A case report. Arch Neurol 34: 785. Fivaz BH, Petney TN (1989). Lyme disease – a new disease in southern Africa? J S Afr Vet Assoc 60: 155–158. Fogelson JL, Krauss W (2008). Compressive and traumatic myelopathies. Continuum, Lifelong Learning Neurol 14: 116–133. Gallo Diop A, Millogo A, Obot I et al. (2006). Neurological disorders associated with malnutrition. In: World Health Organization: Neurological Disorders: Public Health Challenges, WHO, Geneva, pp. 111–126. Galukande M, Muwazi S, Mugisa DB (2005). Aetiology of low back pain in Mulago Hospital, Uganda. Afr Health Sci 5: 164–167. Garcia A, Zanibbi K (2004). Homocysteine and cognitive function in elderly people. CMAJ 171: 897–904. Garcia A, Haron Y, Evans L et al. (2004). Metabolic markers of cobalamin deficiency and cognitive function in normal older adults. J Am Geriatr Soc 52: 66–71. Garin CH, Bujadoux C (1922). Paralysie par les tiques. J Med Lyon 71: 765–767. Gautam MP, Karki P, Rijal S et al. (2005). Pott’s spine and paraplegia. J Nep Med Assoc 44: 106–115. Gessain A, Mahieux R (2012). Tropical spastic paraparesis and HTLV-1 associated myelopathy: clinical, epidemiological, virological and therapeutic aspects. Rev Neurol (Paris) 168: 257–269. G€ org€ ul€ u A, Albayrak BS, G€org€ ul€ u E et al. (2006). Spinal epidural abscess due to Brucella. Surg Neurol 66: 141–147. Graeff-Teixeira C, da Silva AC, Yoshimura K (2009). Update on eosinophilic meningoencephalitis and its clinical relevance. Clin Microbiol Rev 22: 322–348. Harvey AL, Myslinski J, Ortiz L (1998). A case of Nocardia epidural abscess. J Emerg Med 16: 579–581. Healton EB, Savage DG, Brust JC et al. (1991). Neurologic aspects of cobalamin deficiency. Medicine (Baltimore) 70: 229–245. Howard AK, Li DKB, Oger J (2003). MRI contributes to the differentiation between MS and HTLV-1 associated

myelopathy in British Columbian coastal natives. Can J Neurol Sci 30: 41–48. Hudson CP, Hennis AJM, Kataaha P et al. (1988). Risk factors for the spread of AIDS in rural Africa: evidence from a comparative sero-epidemiological study of AIDS, hepatitis B and syphilis in southwestern Uganda. AIDS 2: 255–260. Janmohammandi N, Roushan MRH (2009). False negative serological tests may lead to misdiagnosis and mismanagement in osteoarticular brucellosis. Trop Doct 39: 88–90. Jowi JO, Gathua SN (2005). Lyme disease: report of two cases. East Afr Med J 82: 267–269. Kincaid O, Lipton HL (2006). Viral myelitis: an update. Curr Neurol Neurosci Rep 6: 469–474. Kompoliti A, Gage B, Sharma L et al. (1996). Human T-cell lymphotropic virus type 1-associated myelopathy, Sj€ ogren syndrome, and lymphocytic pneumonitis. Arch Neurol 53: 940–942. Lambertucci JR, Silva LC, do Amaral RS (2007). Guidelines for the diagnosis and treatment of schistosomal myeloradiculopathy. Rev Soc Bras Med Trop 40: 574–581. Leite CC, Jinkins JR, Escobar BE et al. (1997). MR imaging of intramedullary and intradural-extramedullary spinal cysticercosis. Am J Radiol 169: 1713–1717. Lowenstein DH, Mills C, Simon RP (1987). Acute syphilitic transverse myelitis: unusual presentation of meningovascular syphilis. Genitourin Med 63: 333–338. Ludolph AC, Hugon J, Dwivedi MP et al. (1987). Studies on the aetiology and pathogenesis of motor neuron diseases. 1. Lathyrism: clinical findings in established cases. Brain 110: 149. Maharaj JC (1996). Epidemiology of spinal cord paralysis in Fiji: 1985–1994. Spinal Cord 34: 549–559. McDonald JW, Sadowsky C (2002). Spinal cord injury. Lancet 359: 417–425. Misra UK, Nag D, Husain M et al. (1988). Endemic fluorosis presenting as cervical cord compression. Arch Environ Health 43: 18–21. Mosha F, Nicoll A, Barongo L et al. (1993). A population based study of syphilis and sexually transmitted disease syndromes in north-western Tanzania. 1. Prevalence and incidence. Genitourin Med 69: 415–420. Nakamura H, Kawakami A, Tominaga M et al. (2000). Relationship between Sj€ ogren’s syndrome and human Tlymphotropic virus type I infection: follow-up study of 83 patients. J Lab Clin Med 135: 139–144. Newman NJ, Torroni A, Brown D et al. (1994). Epidemic neuropathy in Cuba not associated with mitochondrial DNA mutations found in Leber’s hereditary optic neuropathy patients. Am J Ophthalmol 118: 158–168. Nwadinigwe CU, Anyaehie UE (2011). Iatrogenic pyogenic spondylodiscitis: a case report and a review of literature. Niger J Med 20: 169–171. Olasode BJ, Komolafe IE, Komolafe M et al. (2006). Traumatic spinal cord injuries in Ile-Ife, Nigeria, and its environs. Trop Doct 36: 181–182. Oluwole OSA, Onabolu AO, Link H et al. (2000). Persistence of tropical ataxic neuropathy in a Nigerian community. J Neurol Neurosurg Psychiatry 69: 96–101.

TROPICAL MYELOPATHIES Oluwole OSA, Onabolu AO, Rosling H et al. (2002). Low prevalence of ataxic polyneuropathy in a community with high exposure to cyanide from cassava foods. J Neurol 249: 1034–1040. Oluwole OSA, Onabolu AO, Rosling H et al. (2003). Incidence of ataxic polyneuropathy and its relationship to exposure to cyanide in a Nigerian community. J Neurol Neurosurg Psychiatry 74: 1412–1416. Osuntokun BO (1968). An ataxic neuropathy in Nigeria: a clinical, biochemical and electrophysiological study. Brain 91: 215–248. Palacio LG, Rivera D, Builes JJ et al. (2002). Multiple sclerosis in the tropics: genetic association to STR’s loci spanning the HLA and TNF. Mult Scler 8: 249–255. Poser CM, Poser JC (2006). Neurology in the developing world. Brain 129: 1624–1629. Pot C, Chizzolini C, Vokatch N et al. (2006). Combined antiviral-immunosuppressive treatment in human T-lymphotrophic virus 1-Sj€ogren-associated myelopathy. Arch Neurol 63: 1318–1320. Reik L, Steere AC, Bartenhagen NH et al. (1979). Neurologic abnormalities of Lyme disease. Medicine (Baltimore) 58: 281–294. Richens J, McGill PE (1995). The spondyloarthropathies. Baillieres Clin Rheumatol 9: 95–109. Rogers LM, Boy E, Miller JW et al. (2003). High prevalence of cobalamin deficiency in Guatemalan schoolchildren: associations with low plasma holotranscobalamin II and elevated serum methylmalonic acid and plasma homocysteine concentrations. Am J Clin Nutr 77: 433–440. Roma´n G (1984). Tropical myeloneuropathies. In: P Dyck, P Thomas (Eds.), Peripheral Neuropathy. WB Saunders, Philadelphia, pp. 1322–1331. Roma´n GC (1985). Epidemic neuropathies of Jamaica. Trans Stud Coll Phys Phila Med Hist 7: 261–274. Roma´n GC (1989). Tropical spastic paraparesis and HTLV-1 myelitis. In: Handbook of Clinical Neurology, Viral Disease, Vol. 12. Amsterdam, Elsevier, p. 525. Roma´n GC (1994). An epidemic in Cuba of optic neuropathy, sensorineural deafness, peripheral neuropathy and dorsolateral myeloneuropathy. J Neurol Sci 127: 11–28. Roma´n GC (2003). Neurological complications of HTLV-I infection. In: JH Noseworthy (Ed.), Neurological Therapeutics: Principles and Practice. Vol. 1. Martin Dunitz, London and New York, pp. 962–968. Roma´n GC (2011). The neurology of parasitic diseases and malaria. Continuum, Lifelong Learning Neurol 17: 113–133. Roma´n GC (2005). Nutritional disorders of the nervous system. In: ME Shils, M Shike, AC Ross, B Caballero, RJ Cousins (Eds.), Modern Nutrition in Health and Disease. 10th edn (50th Anniversary Edition). Lippincott Williams & Wilkins, Philadelphia, pp. 1362–1380, Chapter 88. Roma´n GC, Spencer PS, Schoenberg BS (1985). Tropical myeloneuropathies: the hidden endemias. Neurology 35: 1158–1170. Rosling H (1986). Cassava, cyanide, and epidemic spastic paraparesis. Acta Univ Upsal 19: 1–52.

1547

Rosling H, Tylleska¨r T (1996). Konzo. In: RA Shakir, PK Newman, CM Poser (Eds.), Tropical Neurology. Saunders, London, pp. 353–364. Scalabrino G, Buccellato FR, Veber D et al. (2003). New basis of the neurotrophic action of vitamin B12. Clin Chem Lab Med 41: 1435–1437. Schmutzhard E (2007). Eosinophilic myelitis, a souvenir from South East Asia. Pract Neurol 7: 48–51. Singh A, Jolly SS, Bansal BC et al. (1963). Endemic fluorosis: epidemiological, clinical and biochemical study of chronic fluorine intoxication in Panjaei (India). Medicine (Baltimore) 42: 229–246. Solagberu BA (2002). Spinal cord injuries in Ilorin, Nigeria. West Afr J Med 21: 230–232. Song K-J, Yoon SJ, Lee K-B (2012). Cervical spinal brucellosis with epidural abscess causing neurologic deficit with negative serologic tests. World Neurosurg 78: 375. Spencer PS, Hugon J, Ludolph A et al. (1987). Discovery and partial characterization of primate motor-system toxins. Ciba Found Symp 126: 221. Stabler SP, Allen RH (2004). Vitamin B12 deficiency as a worldwide problem. Annu Rev Nutr 24: 299–326. Stambos V, Brussen KA, Turnbull A et al. (2001). Report of the Australian National Polio Reference Laboratory, 1 July to 31 December 2000. Commun Dis Intell 25: 54–58. Strom T, Schneck SA (1991). Syphilitic meningomyelitis. Neurology 41: 325–326. Th€ one J, Hohaus A, Bickel A et al. (2007). Severe spinal cord ischemia subsequent to fibrocartilaginous embolism. J Neurol Sci 263: 211–213. Timmermans M, Carr J (2004). Neurosyphilis in the modern era. J Neurol Neurosurg Psychiatry 75: 1727–1730. Torabi AM, Quiceno M, Mendelsohn DB et al. (2004). Multilevel intramedullary spinal neurocysticercosis with eosinophilic meningitis. Arch Neurol 61: 770–772. Toro G, Roma´n GC, Navarro de Roma´n LI (1983). Neurologı´a Tropical. Aspectos Neuropatolo´gicos de la Medicina Tropical. Printer Colombiana, Bogota´. Toro G, Roma´n GC, Navarro-Roma´n I et al. (1994). Natural history of spinal cord infarction caused by nucleus pulposus embolism. Spine 19: 360–366. Tosi L, Rigoli G, Beltramello A (1996). Fibrocartilaginous embolism of the spinal cord: a clinical and pathogenetic reconsideration. J Neurol Neurosurg Psychiatry 60: 55–60. Turgut M (2001). Spinal tuberculosis (Pott’s disease): its clinical presentation, surgical management, and outcome. A survey study on 694 patients. Neurosurg Rev 24: 8–13. Tylleska¨r T (1994). The causation of konzo. Studies on a paralytic disease in Africa. Acta Univ Upsal 43: 1–67. Tylleska¨r T, Banea M, Bikangi H et al. (1992). Cassava cyanogens and konzo, an upper motor neuron disease found in Africa. Lancet 339: 208–211. Vidal JE, Sztajnbok J, Seguro AC (2003). Eosinophilic meningoencephalitis due to Toxocara canis: case report and review of the literature. Am J Trop Med Hyg 69: 341–343.

1548

G.C. ROMA´N

Vogel T, Dali-Youcef N, Kaltenbach G et al. (2009). Homocysteine, vitamin B12, folate and cognitive functions: a systematic and critical review of the literature. Int J Clin Pract 63: 1061–1067. Wallin MT, Kurtzke JF (2004). Neurocysticercosis in the United States: review of an important emerging infection. Neurology 63: 1559–1564. WHO Schistosomiasis. www.who.int/mediacentre/factsheets/ fs115/en/index.html. Wolters M, Strohle A, Hahn A (2004). Cobalamin: a critical vitamin in the elderly. Prev Med 39: 1256–1266.

Yoshinari NH, Oyafuso LK, Monteiro FG et al. (1993). Lyme disease. Report of a case observed in Brazil. Rev Hosp Clin Fac Med Sao Paulo 48: 170–174. Zellner H, Maier D, Gasser A et al. (2010). Prevalence and pattern of spinal pathologies in a consecutive series of CTs/ MRIs in an urban and rural Tanzanian hospital – a retrospective neuroradiological comparative analysis. Wien Klin Wochenschr 122 (Suppl 3): 47–51.

Tropical myelopathies.

A large number of causal agents produce spinal cord lesions in the tropics. Most etiologies found in temperate regions also occur in the tropics inclu...
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