Magnetic Resonance Imaging of Neurological Diseases in Tropics Rakesh K Gupta, Sunil Kumar
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1Introduction2

Overview of Tropical Diseases of Central Nervous SystemCHAPTER 1

Kashi N Prasad,
Manodeep Sen
 
INTRODUCTION
Tropical diseases of the central nervous system (CNS) can be classified into two groups: infective and noninfective. Infective CNS diseases, though preventable, yet remain a major cause of morbidity and mortality in the tropics. A large variety of infectious agents can invade the CNS and cause damage. Specific etiologic diagnosis of CNS infections continues to be a major challenge to the medical fraternity. Acute bacterial causes of CNS infections can be diagnosed in majority of cases, but in aseptic meningitis and encephalitis, the etiologies more often remain unsettled.1,2 Possible reasons may be the involvement of wide variety of organisms, suboptimal sample available for processing, some agents are not detected by available diagnostic methods, and some molecular methods, though available are too expensive. Polymerase chain reaction (PCR) based techniques and neuroimaging have revolutionized the specific diagnosis of many CNS infections but due to involvement of many bacterial, viral, parasitic and fungal pathogens with almost similar but polymorphic presentations the diagnostic dilemma continues, especially in subacute and chronic infections. Information on microbes causing disease in particular region is important so that triaging of many tests based on likely pathogens can be adopted. This article is not intended to discuss all the infective tropical diseases of CNS in details; rather it is an overview that includes common bacterial, viral, parasitic and fungal infections of the CNS in the tropics.
 
BACTERIAL INFECTIONS
The organisms that produce bacterial infections of the CNS in tropical areas are similar to those existing as in the rest of the world.
 
Acute Bacterial Meningitis
It is an important cause of morbidity and mortality both in children and adults. The etiologies of bacterial meningitis are summarized in Table 1.
Due to vaccine related decline in Haemophilus influenzae disease, Streptococcus pneumoniae and Neisseria meningitidis remain important pathogens in children and young adults.3 Group B Streptococcus is the most common pathogen associated with meningitis in newborns. Listeria monocytogenes is also recognized as a significant cause of meningitis in newborns and the elderly. CNS listeriosis can manifest as brain abscess in 10% infected patients especially in immunocompromised hosts. Conventional diagnostic tests for bacterial meningitis include cerebrospinal fluid (CSF) cell count, staining and culture on appropriate media; other tests are antigen detection in CSF, latex amoebocyte limulus assay for Gram negative organisms and bacterial PCR. Biochemical tests include protein and glucose levels in CSF.
 
Neurotuberculosis
Neurotuberculosis constitutes 1% of all tuberculosis and 10–15% of the extrapulmonary tuberculosis cases; majority (over 40%) in children.4 CNS tuberculosis also accounts for 1.5–3.2% of all tuberculosis related deaths.5 CNS tuberculosis remains common, and despite the availability of effective antituberculous therapy, the classical syndromes—spinal cord compression from tuberculous osteitis, tuberculous meningitis (TBM) and intracranial tuberculomas continue to cause significant morbidity and mortality. TBM constitutes 70–80% of cases of all neurotuberculosis.6 Classification of CNS tuberculosis based on location and pathology is shown in Table 2.4
Thickening and intense enhancement at basilar region and sylvian fissure with ventricular enlargement and infarcts are the characteristic features of TBM on imaging.4
Table 1   Etiologies of bacterial meningitis
Meningitis
Acute (neutrophilic pleocytosis)
Neisseria meningitidis
Streptococcus pneumoniae
Haemophilus influenzae
Streptococcus agalactiae (Group B)
Escherichia coli and other gram –ve bacilli*
Listeria monocytogenes
Subacute-chronic (predominantly lymphocytic pleocytosis)
Mycobacterium tuberculosis
Nocardia asteroides complex
Brucella spp.
Leptospira interrogans
Treponema pallidum
Borrelia burgdorferi
* Other gram-negative bacilli include Enterobacteriaceae, Pseudomonas aeruginosa and other nonfermenting gram-negative bacilli.
Table 2   Classification of central nervous system (CNS) tuberculosis
S. No.
Classification of CNS tuberculosis
a.
Intracranial
1.
Tuberculous meningitis (TBM)
2.
TBM with miliary tuberculosis
3.
Tuberculous encephalopathy
4.
Tuberculous vasculopathy
5.
Space-occupying lesions
b.
Spinal
1.
Pott's spine and Pott's paraplegia
2.
Tuberculous arachnoiditis (myeloradiculopathy)
3.
Nonosseous spinal tuberculoma
4.
Spinal meningitis
Intracranial tuberculoma, single or multiple, remains the most common cause of a space-occupying lesion in the tropics. In developing countries young adults and children are predominantly affected while in developed countries they are more common in older patients.4 Obstructive hydrocephalus may develop at any stage of the illness, sometimes acutely; it is the most likely explanation for sudden neurological deterioration and should be treated promptly by surgical drainage.
Microbiological diagnosis is based on identification of acid fast bacilli (AFB) in the CSF through smear examination and culture. Both the methods have low sensitivity due to paucity of acid fast bacilli (AFB) in cases with CNS tuberculosis. Standard staining techniques such as Ziehl-Neelsen, Kinyoun, or auramine-rhodamine detect approximately 100 AFB/ml of CSF.7 Cisternal and ventricular CSF appear to have higher culture sensitivity. Minimum 6 ml of CSF fluid should be centrifuged and examined microscopically for a period of 30 min to improve the detection. Rapid broth culture with automated systems like MGIT (Becton Dickinson, Microbiology Systems, Cockeysville, Md), EPS system (Trek Diagnostic Systems, Inc., Westlake, Ohio), BACTEC 9000 TB series (Becton Dickinson Diagnostic Instruments, Sparks, Md.) have increased the sensitivity and turn-around time for detection of Mycobacterium tuberculosis. Several adjunctive tests shown in Table 3 have been advocated for detection of TBM with variable sensitivity and specificity.8
 
Brucell osis
Brucellosis occurs in many tropical and subtropical areas and the central nervous system may be affected in up to 5% of patients.9 It can cause an acute meningoencephalitis with papilloedema, convulsions and coma. Spinal presentation occurs with spastic or flaccid paraparesis due to cord compression or myeloradiculopathy, and central involvement with hemiparesis and ataxia. Diagnosis depends on blood or CSF culture for Brucella, or more commonly on enzyme-linked immunosorbent assay (ELISA) for antibodies in blood and CSF. Treatment with rifampicin, tetracycline and streptomycin should be for 3 months in those presenting with the subacute or chronic forms.
 
Spirochetes
Neurosyphilis is on the rise and is increasingly occurring in the era of HIV infection. Frequently occurring spirochaetal infections affecting the nervous system include borreliosis or relapsing fever (Borrelia recurrentis, louse-borne; B. duttonii, tick-borne), usually presenting as a febrile meningoencephalitis. Leptospirosis may affect any part of the nervous system, including an acute neuropathy.10 Lyme disease (B. burgdorferi) is spread to man by infected ticks. It is the leading vector-borne disease in the USA and mainly in temperate climates. The neural manifestations span from meningitis, encephalitis, focal cranial neuropathies, radiculitis neuropathy, encephalopathy and postborreliosis syndromes. Diagnosis is based on dark field microscopic examination, culture, PCR and IgG/IgM antibodies in CSF/serum.
 
Rickettsia
It usually presents as acute meningoencephalitis. They are transmitted to man via the bites of ticks or mites, distinctive eschar at the site of the bite may suggest the diagnosis. Mediterranean spotted fever (Rickettsia conorii) in Africa, Asia and the Mediterranean basin; scrub typhus (R. tsutsugamushi) in Asia and the Pacific; typhus (R. prowazekii) and Q fever (Coxiella burnetii) are ubiquitous.5
Table 3   Adjunctive tests for diagnosis of tuberculous meningitis
S. No.
Tests
Sensitivity
Specificity
Time required
a.
Biochemical
1.
Radiolabeled bromide partition ratio
90–94%
88–96%
48 hours
2.
CSF adenosine deaminase level
73–100%
71–99%
< 24 hours
3.
CSF tuberculostearic acid level
95%
99%
< 24 hours
b.
ELISA
1.
CSF mycobacterial antigen
79–94%
95–100%
< 24 hours
2.
CSF mycobacterial antibody
27–100%
94–100%
< 24 hours
3.
DNA analysis by PCR
83–100%
80–100%
< 24 hours
All patients manifest high fever, rash and headache, with meningoencephalitis developing during the second week of the illness. More than 30 million cases of louse-borne typhus occurred during and immediately after World War I, causing an estimated 3 million deaths. The explosive spread of the brutal epidemic of louse-borne typhus within crowded human populations in the wake of war, famine, flood, and other disasters made a deep impression on the commanders of the Russian Red Army, and by 1928, R. prowazekii was transformed into a battlefield weapon. Subsequently, the Japanese Army successfully tested biobombs, containing R. prowazekii, causing outbreaks of typhus.11 Thus, the precedent exists in utilizing pathogenic rickettsiae in warfare with bioterrorism potential. CSF examination is rarely helpful and treatment should be started on clinical suspicion. It usually responds to tetracycline or chloramphenicol.
 
Brain Abscess
The incidence of brain abscess is as low as 1–2% in the developed world, while in the developing countries it reported to be as high as 8% of all intracranial lesions.12 Due to improvement in diagnostic modalities including neuroimaging and surgical techniques, the mortality in many countries is below 10%; however it still remains a significant problem in many tropical countries with reported mortality between 17% and 32%.13 Brain abscess most commonly originates from the contiguous site of an existing infection such as chronic otitis media, mastoiditis, sinusitis or dental caries, but it can also occur directly after penetrating head injury, neurosurgical procedures or hematogenously as in children with cyanotic congenital heart disease.13 Viridans streptococci, Staphylococcus aureus, Bacteroides fragilis group/species and Peptostreptococcus species are the common etiologic agents.13 Patients with gram-negative infections are reported to have higher mortality than Gram positive infections.13 Culture of pus immediately after aspiration in an automated system yields good results. Gram stain coupled with culture can guide the neurosurgeons better to treat their patients more rationally. Tubercular brain abscesses are extremely rare and reported in 4 to 7.5% of patients with CNS tuberculosis.4 It is possible to differentiate tuberculous abscesses from pyogenic or fungal abscesses by using different MR techniques.14,15
 
VIRAL INFECTIONS
Herpes, entero, and arbo viruses are the major agents causing CNS infections.16 Entero and herpes viruses are also well known cause of aseptic meningitis both in adults and children. Subacute sclerosing panencephalitis (SSPE), a sequaele of measles is still relatively common and fatal in many parts of the Middle East, Far East, India, Africa and South America. Acute viral encephalitis, due to direct viral invasion of the brain parenchyma, is indistinguishable clinically from the postinfectious encephalitides. Worldwide, viruses are the most common cause of encephalitis. Herpes simplex virus is the most common cause of fatal nonepidemic encephalitis. Other viruses include cytomegalovirus, Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and human herpes virus-6 (HHV-6). In recent years, special attention has been given to VZV in CNS infections, and probably this virus is underestimated as cause of both aseptic meningitis and encephalitis with vascular complications.1 VZV may spread from its latent state in spinal root ganglia to CNS and induce intrathecal antibody production. The virus may also be found in CSF with or without skin manifestations. Influenza, adeno, parainfluenza and respiratory syncytial viruses are also identified as etiologic agents of CNS infections; some CNS infections are also associated with rotavirus with demonstrable intrathecal antibodies.1 The arboviruses cause epidemic encephalitides in many parts of the world. The majority is perpetuated by zoonoses, often obtained from birds and smaller vertebrates; transmission is by an arthropod vector such as a mosquito or tick. Many patients recover spontaneously after a mild attack; others may deteriorate and die within days or weeks. The 6clinical features are prodromal myalgia, fever and malaise, then headache, mental changes, drowsiness, with or without signs of meningeal irritation; focal neurological abnormalities such as behavioral disturbances, mood, disorientation, deterioration of speech, level of consciousness, fits (focal or generalized), raised intracranial pressure and a deepening coma. Japanese encephalitis (JE) is a mosquito-borne arboviral infection which still claims many lives in South-East Asia. The virus is antigenically related to the flaviviruses like West Nile virus. The illness is usually severe, and fatal in about 25% of cases, with neuropsychiatric sequelae in a further 30%. It mainly affects the young, but a shift now to the elderly may be due to early immunization. Recently it has been shown that a novel attenuated live vaccine SA 14-14 2 is highly effective and the safety of the vaccine is due to high degree of neuroattenuation, and unlikely reversion to neurovirulence.17
There may be no specific features on computed tomography (CT) or magnetic resonance imaging (MRI), and the EEG and cerebrospinal fluid (CSF) may not be diagnostically helpful. The demonstration of antibodies in parallel on serum or CSF may confirm the true etiological agent. The serum/CSF antibody ratio is diagnostic in many cases. Specific IgM antibody in CSF appears promising, especially if immunofluorescence (IFA) test is used. The benefits of IFA are that the test is sensitive, rapid and can be performed on minimal amount of CSF about 25 μl. PCR on CSF is the emerging modality to diagnose viral infections. Four sets of primers for enterovirus, HSV, VZV and EBV accounted for 96% positive results in the United Kingdom.18 Other viruses that should be included in the protocol are CMV, HHV-6. Virus culture of CSF is an established modality of diagnosis but sensitivity is very low. Isolations of viruses from extracranial sources like stool, respiratory samples or antigen detection in throat samples are indirect evidences of CNS infections.
The other viruses that can involve CNS with low frequency are described below in brief:
 
Poliomyelitis
Polio has spread from northern Nigeria across much of central Africa and into the Middle East and as far as Indonesia.19 An outbreak of polio in the northern Indian states, which started in 2005, quadrupled in 2006. Moreover, by mid-September 2006, cases of polio were confirmed in Angola, Bangladesh, Congo, Nigeria, and Nepal. Huang and colleagues recommend carrying out studies on vaccine virus pe rsistence in tropical developing countries where transmission of OPV viruses is likely to be more intense.20
 
Dengue
Dengue, especially the hemorrhagic variety, still causes considerable morbidity and fatality in South-east Asia. Dengue virus is a flavivirus transmitted by the bite of the mosquito. Three distinct neurological syndromes have been reported during dengue infection: (1) acute non-specific neurological symptoms (headache, retrobulbar pain, mood change, etc.), (2) acute encephalitic or focal neurological symptoms (spastic paraparesis, seizures, mono- or polyneuropathy, etc.) and (3) postinfectious neurological complications (transverse myelitis, mononeuropathies).21
 
Lassa Fever
Lassa fever, an acute hemorrhagic febrile illness occurring in West Africa, causes a fatality of up to 20%. It is caused by an arenavirus spread by a rodent (Mastomys natalensis); it causes a wide spectrum of clinical manifestations, from asymptomatic to fatal illness, and is often associated with neurological manifestations during the acute disease or in early convalescence. Delirium, convulsions and coma occur in critically ill patients.
 
Rabies
Rabies is acute, progressive, fatal encephalitis caused by viruses in the family Rhabdoviridae, genus Lyssavirus. Rabies is transmitted usually by saliva from infected bites of dogs, foxes, bats and others. After its onset, the disease presents as encephalitis (in 80%) with hydrophobia or a paralytic syndrome (in 20%), which is always fatal. Bat rabies is a growing concern for both public and animal health.
 
HIV
A total of 25–28 million people with HIV live in sub-Saharan Africa. One-third of HIV-infected patients have at least one neurological complication. All parts of the CNS, peripheral nerves and roots and muscles may be involved in the course of HIV infection. HIV itself can have an impact on the nervous system as well as complications related to antiretroviral treatment. Highly active antiretroviral therapy (HAART) can stop or reduce the process of destruction of the immune system induced by the virus, but cannot protect the brain from HIV. Preliminary data indicate that the brain may serve as a long-term reservoir for the virus, and neuroinflammatory and neurodegenerative changes may continue despite HAART.22
 
Human T Lymphotropic Virus
Human T lymphotropic virus (HTLV-1) is a human retrovirus and main modes of transmission are blood-borne, sexual and mother-to-child. Japan, Africa, the Caribbean Islands and South America have emerged as the areas of highest prevalence.23 There are 3 types of HTLV-1 viruses based on envelope sequencing: ‘cosmopolitan’, ‘central African’ and ‘Australo-melanesian’.7
Only a small proportion of the individuals carrying the virus show signs of HTLV-1-associated myelopathy. HTLV-1 is the etiological agent for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP appears in children and adults, but more often age of onset is between 30 and 60 years, and is characterized by slowly progressive spastic paraparesis with urinary disturbance and high levels of Th1 cytokines, interferon-γ and tumor necrosis factor.24
 
PARASITIC INFECTIONS
A wide variety of parasites both protozoa and helminths are responsible for CNS infections in the tropics. Immunosuppression associated with HIV infection and following organ transplantation increases the susceptibility to opportunistic infections. Frequent international travels pose increased threat for the spread of parasitic infections that were earlier limited to particular tropical regions. Some important parasitic diseases of the CNS are reviewed below:
 
Cerebral Malaria
Malaria is caused by intracellular protozoan parasite of Plasmodium species and transmitted by the bites of female Anopheles mosquito. Cerebral malaria is a major life-threatening complication of Plasmodium falciparum in humans. P. falciparum is the predominant species in tropical countries, whose mortality remains high and over 80% of these cases occur in Africa.25 The incidence of malaria is increasing because of drug resistance by the parasite and insecticide resistance by the vector associated with social and environmental changes. Major neurologic manifestations of cerebral malaria are generalized seizures, coma, cranial nerve and cognitive dysfunctions. Severity of the disease increases in immunocompromised hosts. Although the pathogenesis of cerebral malaria is complex and relatively unknown, the sequestration and binding of the infected red blood cells to the cerebral microvasculature endothelium and the disappearance of the infected cells with mature stage of the parasite from the peripheral blood are likely to play key role in the pathogenesis. Patients with P. falciparum malaria having altered consciousness should be examined for cerebral malaria. Detection of the parasite in thick and thin blood smear by Giemsa or Leishman stain is the gold standard. Immunochromatographic test for detection of parasite specific histidine rich protein and lactate dehydrogenase enzyme in serum is commercially available and frequently being used. Cerebral malaria is an acute emergency that warrants immediate treatment with an intravenous infusion of artesunate or drip infusion of quinine.
 
Trypanosomiasis
Two major diseases have been identified: human African trypanosomiasis (HAT), known as sleeping sickness and American trypanosomiasis, known as Chagas’ disease. HAT produces progressive CNS damage, which if untreated results in death. Involvement occurs within a few weeks in the case of Trypanosoma rhodesiense, but usually takes much longer in the case of T. gambiense, i.e. months or even years. Brain involvement is caused mainly by cytokines (interferon-α, tumor necrosis factor-α, and IL-10), nitric oxide and endothelial cell apoptosis.26 Treatment for the early stage of HAT involves the drugs pentamidine and suramin. In the second stage of the disease, during which the trypanosomes reside in the cerebrospinal fluid, treatment is exclusively on the arsenical compound melarsoprol, which crosses the blood-brain barrier. However, there occurs a severe post-treatment reactive encephalopathy in 10% of cases with up to 50% mortality.
 
Amebiasis
Infection of the CNS by amoebae is unusual. Entamoeba histolytica is an intestinal parasite and the causative agent of amebiasis in developing countries. E. histolytica can cause single or multiple cerebral abscesses which are noted on neuroimaging and may be clinically silent. Indirect hemagglutination antibody assay can be used for the diagnosis. Early treatment with metronidazole followed by rifampicin and tetracycline may improve both symptoms and radiographic images. Persons with HIV/AIDS are at significantly higher risk of E. histolytica infection.
Three free-living amoebae—Naegleria fowleri, Acanthamoeba species and Balamuthia mandrillaris are recognized CNS pathogens. N. fowleri is the causative agent for primary amoebic meningoencephalitis (PAM), while Acanthamoeba and Balamuthia can cause granulomatous amoebic encephalitis (GAE).27 These amoebae are found in soil, water and air samples from all over the world. N. fowleri is a thermophilic amoeba that grows well in tropical and subtropical climates. The PAM is characterized by an acute fulminant meningoencephalitis leading to death 3–7 days after exposure. The GAE is usually seen in debilitated, malnourished individuals and in patients with AIDS. Clinical manifestations include headache, fever, seizures, hemiparesis and coma leading to death. Clinical course is insidious and may mimic bacterial meningitis or tuberculous meningitis. The IFA test is relevant when used in patients whose clinical, laboratory and radiological findings suggest amoebic encephalitis. A sequential regime of anti-amoebic drugs, such as azithromycin, pentamidine, itraconazole, and flucystone is 8recommended. A recently recognized new human pathogen Sappinia diploidea may also lead to encephalitis.28
 
Toxoplasmosis
Toxoplasma gondii is an intracellular protozoan and cat is the definitive host. Transmission to humans occurs in several ways:
  1. Ingestion of undercooked infected pork and meat.
  2. Ingestion of oocyst through direct fecal-oral contamination from soil.
  3. Organ transplantation or blood transfusion.
  4. Transplacental transmission from mother to foetus and
  5. Accidental inoculation of tachyzoites.
    Symptomatic CNS toxoplasmosis rarely develops during primary infection in normal hosts. As such toxoplasma encephalitis is a rare entity in immunocompetent human host; however it is being increasing reported in immunocompromised hosts.29 Since the dissemination to brain is hematogenous, the toxoplasma lesions are close to the corticomedullary junction, within the thalamus and basal ganglia, where small end-arteries are embolized. Lesions are typically supratentorial, again possibly reflecting the dominant distribution of blood flow, but cerebellar lesions are also seen.
 
Microsporidiosis
Microsporidia are under consideration for reclassification from protozoa to fungi. They are single celled intracellular obligate microbes and more than 20 genera of human importance have been reported. Several species can cause disseminated infections including Trachipleistophora that have been associated with encephalitis and death. Disseminated infections with CNS involvement can occur in HIV infected populations (when the CD4+ counts decrease to < 50/mm3), following renal, pancreas and bone marrow transplantation.30 Although the CNS symptoms depend on the location of infection, seizures are the most common manifestation, often associated with sinusitis and keratoconjunctivitis in HIV patients. Microsporidia are transmitted via contaminated water, fecal-oral route and air droplets. They possess resilient spores with polar apparatus capable of injecting the infectious sporoplasm into the host cell cytoplasm. Diagnosis is made by demonstrating the organisms in body fluids or tissue biopsies. Electron microscopy can help in species identification. CSF may show neutrophilic pleocytosis and occasionally microsporidia. Spores are often present in peripheral blood during CNS infection. PCR is highly sensitive but not widely used. Brain imaging shows multifocal contrast enhancing lesions; meningeal enhancement has been reported in a transplant patient with CNS involvement.
 
Neurocysticercosis
Neurocysticercosis (NCC) caused Taenia solium larva is a major public health problem in many parts of the world particularly in Latin America, Africa and Asia. Neurocysticercosis is common in communities where pigs are allowed to roam freely, the residents consume insufficiently cooked pork and the basic sanitary facilities are lacking. It is identified as the most common helminthic parasitic infection of the CNS and the single most common cause of community acquired active epilepsy. Neurocysticercosis is increasingly diagnosed in affluent countries owing to human migration from endemic areas. Recent MRI based Indian studies suggest that the disease burden in India surpasses many other developing countries and possibly the disease is grossly under reported in North India. In a recent survey in pig farming community of Lucknow district, active epilepsy was identified in 5.8% populations and 48.3% of them fulfilled either definitive or probable diagnostic criteria for NCC.31 Asymptomatic NCC was also found to be very high in the same community; 29% family members of the symptomatic NCC patients harboured cysticerci in their brain.32 Enhanced proinflammatory immune response and expression of adhesion molecules were found to be associated with symptomatic NCC.33 Overall NCC was identified as the cause of active epilepsy in 26.3–53.8% in the developing world including Latin America.34
Seizures are the most common symptom, occurring in 70–90% of patients with NCC. When cysticerci lodge within the ventricular system, acute intracranial hypertension secondary to hydrocephalus may develop. Cysts in the subarachnoid space may grow to large sizes (giant cysts) causing intracranial hypertension with hemiparesis, partial seizures or other focal neurological signs. Racemose cysts in the basal cisterns can cause an intense inflammatory reaction at the base of the brain. Approximately 60% of the cases develop obstructive hydrocephalus. Some cases develop chronic cysticercosis meningitis, with headache and stiff neck. Ventricular and basal cisternal locations are considered to be malignant forms of NCC.35 About 1.5–3% of all cases develop spinal NCC. Because the clinical presentation of NCC is non-specific, diagnosis has been difficult. Definitive or probable diagnosis of NCC related active epilepsy in patients is based on clinical, immunological, neuroimaging (CT/MRI) and epidemiological criteria.36,37 CT and MRI have greatly facilitated the diagnosis of NCC. Serological tests for cysticercosis are improving. A monoclonal antibody-based antigen detection enzyme-linked immunosorbent assay has been developed. The test is sensitive (85%) for detection of cysticercus antigen in CSF. Lymphocyte transformation test and MTT assays are the other emerging tests for diagnosis of NCC.38 Recently it has been demonstrated that the PCR diagnosis of T solium DNA in the CSF may be a strong support for the diagnosis of neurocysticercosis.399
The management of NCC can be medical (anthelmintic drugs and corticosteroids) or surgical (removal of the cyst or replacement of CSF shunt). Optimal management depends on the location and the stage of the cysts.35 Albendazole and praziquantel are effective drugs for the treatment of NCC. However, there is controversy about their role in several forms of the disease. There is a strong consensus between experts that there is no role for antiparasitic drugs in patients with only calcified lesions. Studies suggest that patients with single enhancing lesions will do well regardless of antiparasitic therapy. Antiparasitic drugs are contraindicated in patients with cerebral edema (cysticercal encephalitis) and most experts strongly recommend antiparasitic therapy in patients with multiple subarachnoid cysticerci or giant cysticerci. In patients with ventricular cysticerci, endoscopic removal is the preferred therapy but placement of a ventricular shunt followed by antiparasitic therapy is an acceptable alternative.
 
Filariasis
Central nervous system involvement may be due to Loa loa or Onchocerca volvulus. Loiasis can cause meningoencephalitis with microfilariae in the CSF. Severe adverse events following ivermectin treatment may occur in people with parasitic load, especially in Loa loa encephalopathy. Onchocerciasis (river blindness) is a filarial infection which causes blindness and debilitating skin lesions. The disease occurs in 37 countries, of which 30 are found in Africa (the most affected in terms of distribution and the severity of the clinical manifestations of the disease), six in the Americas and one in the Arabian Peninsula.40 In rural areas of central Cameroon and West Uganda, it was found that epilepsy was closely linked to onchocerciasis.41 A higher incidence of epilepsy in zones of high endemicity of onchocerciasis may be due to various risk factors including genetic factors and low socioeconomic status. The possibility of a relationship between epilepsy and onchocerciasis might explain the presence of O. volvulus in the CNS and immunological mechanisms involving cross-reactive immunization or cytokine production during infection. In many areas of Africa, where human onchocerciasis is endemic, there are now programs for mass treatment with ivermectin. However, ivermectin is a microfilaricide and does not kill the adult worms. Since it does not cross the blood-brain barrier, the drug is unlikely to have direct pro- or anti-convulsive activity.
 
Nematode Infections
The gender Gnathostoma includes many species, the most frequent being Gnathostoma spinigerum. Human gnathostomiasis is endemic in some countries of South-east Asia, and Latin America. Since the beginning of the 1980s, there have been an increasing number of cases of gnathostomiasis described in Western countries in travellers returning from endemic countries.42 The disease develops due to the consumption of raw or insufficiently cooked meat or fish. Gnathostomiasis is a cause of cutaneous and/or visceral larva migrans syndrome. The most common neurological manifestations include encephalitis, myelitis, radiculomyelitis, radiculitis and subarachnoid hemorrhage.43 The main laboratory finding is eosinophilia in blood and CSF. Some patients present with a curious and fatal multifocal neurological illness.
Angiostrongylus cantonensis (rat lung worm) similarly affects those in South-east Asia who consume poorly cooked snails, prawns and crabs. Neurological complications include meningitis, papilledema and extraocular palsies with an eosinophilic CSF pleocytosis. Brain abscesses may occur and CT shows well-circumscribed enhancing lesions. Both these nematodes are treated with albendazole and steroid.
Strongyloides stercoralis is another nematode which affects the nervous system with eosinophilic meningitis. HIV and tropical infections affect each other mutually. At present, there is a concept that strongyloides dissemination in endemic countries may be as a manifestation of HIV-associated immune reconstitution disease.44
 
Hydatid Disease
Cerebral hydatid disease is very rare and usually secondary. The vast majority of patients affected are children. A cerebral hydatid cyst is always solitary unless the primary site is the brain; CT and MRI may reveal diagnostic daughter cysts. Headache, vomiting and seizures are predominant symptoms in children, whereas focal neurological deficits are most common in adults. Intracranial hydatid cysts should always be surgically removed without rupture; the outcome remains excellent in these cases. Treatment with albendazole is beneficial both pre- and postoperatively. A spinal hydatid disease is a rarity. In spinal hydatidosis, the cysts are usually multiple and extradural, and paraplegia may result.45 In endemic areas, the clinician should include spinal hydatid disease as part of the differential list for paraplegia and consider performing neuroimaging.
 
Schistosomiasis
The longest-known parasite of man—continues to afflict mankind and it is believed that at present more than 200 million people worldwide are affected. Of the Schistosoma species, S. mansoni, S. heamatobium and S. japonicum are the most important to man and the most widely distributed. Schistosomiasis is endemic in parts of South America, sub-Saharan Africa, the Middle East, and some Caribbean islands.46 Disorders of the liver and gastrointestinal tract are the most common clinical manifestations. Neuroschistosomiasis (NS) 10develops through eggs or by anomalous migration of the parasite. More common neurological manifestations of spinal NS are transverse myelitis and myeloradiculopathy. Cerebral NS usually manifests with symptoms of increased intracranial pressure associated with focal neurological signs. Betting et al described NS manifested by partial epileptic seizures caused by a granulomatous lesion due to S. mansoni.47 Antischistosomal drugs, corticosteroids and surgery are the resources for treating NS. The diagnosis of cerebral NS is established by biopsy of the nervous tissue and spinal NS is usually diagnosed according to a clinical criterion. The microscopic examination of excreta remains the gold standard for the diagnosis of schistosomiasis. Eosinophilia in the CSF and the CT and MRI findings may clinch the diagnosis of NS. Praziquantel (PZQ) is active against all schistosoma species. However, the drug has little or no effect on eggs and immature worms. Moreover, decreased susceptibility to PZQ has been observed in several countries and the prospects for developing an effective vaccine are encouraging.
 
Trichinosis
This parasitic disease, which develops after ingestion of undercooked meat contaminated with larvae of Trichinella spiralis, occurs both in tropical and temperate climates, and apparent outbreaks are still reported worldwide.48 The acute illness, with fever, headaches, myalgia, weakness and malaise, arthralgia, periorbital edema, nausea and diarrhea with a marked blood eosinophilia, increased serum muscle enzymes and specific antibodies, is well known. Turk et al reported a benign course and a milder clinical picture of trichinellosis in children than adults.49 Neurological manifestations occurred in 10–15% of the diseased. There could be a serious diagnostic problem in the absence of corresponding epidemiological data and typical symptoms and signs of the disease. Neurotrichinosis may manifest with clinical symptoms of meningitis, encephalitis, polyradiculoneuritis, myasthenia gravis and diseases of the connective tissue involving the nervous system. Brain lesions in trichinosis have been defined on CT and MRI as multifocal small lesions located in the cerebral cortex and white matter.49 Early diagnosis and prompt treatment with anthelmintic therapy such as mebendazole with corticosteroids is mandatory.
 
Paragonimiasis
Paragonimiasis is a typical food-borne parasitic disease that is common in South-East Asia, the Far East, Latin American and Africa. Recently, however, this disease has been seen in many parts of the world, largely due to increase in the numbers of immigrants and overseas travelers. Paragonimiasis westermani is a typical digenetic parasite. Cerebral paragonimiasis (CP) is not rare, but pleuropulmonary manifestations are the most prevalent. CP cases are more frequent in the Far East, especially Korea. It presents as an intracranial space-occupying lesion. Brain MRI shows a single or multiple conglomerated lesions.50 The parasite is transmitted to man through ingestion of crab and crayfish; the metacercariae travel to the lungs and mature. The adult can live in the lung for several years and is usually asymptomatic. Neurological presentation is due to cerebral involvement as a result of the development of cysts in ectopic sites; various intracranial sites can be affected. The diagnosis is based on the identification of parasite eggs in sputum, feces and pleural fluid and on ELISA serology. Studies suggest that triclabendazole is the most effective and best tolerated drug for the treatment of food-borne trematode infections.
 
FUNGAL INFECTIONS
 
Cryptococcosis
Cryptococcosis is a systemic infection caused by an encapsulated yeast fungus, Cryptococcus neoformans. Its distribution is worldwide and it generally presents with meningitis or some other manifestation of extrapulmonary dissemination. While it may cause disease in otherwise healthy individuals, it is also a pathogen of patients with defective T lymphocyte function, such as patients with AIDS, lymphoma or those receiving systemic steroid therapy.
There are two variants of C. neoformans: C. neoformans var. neoformans and C. neoformans var. gattii. The neoformans variety causes disease in immunocompromised patients including those with AIDS, and is found in most countries. Its ecological niche appears to be soil or areas where there are large amounts of pigeon excreta, from which this fungus can be isolated. The presumed route of entry is via inhalation. The gattii form is seen mainly in tropical areas and generally occurs in healthy individuals. It has been reported from Africa, the Far East, Papua New Guinea and Australia. This organism has only recently been isolated from the environment debris of certain species of Eucalyptus. In addition to the differences in distribution there are possible differences in their clinical behavior, apart from the predilection of the neoformans variety for patients with AIDS.
Infection rates in the tropics are not known and appear to be variable, even in patients with AIDS. There is evidence that in Zaire about 12% of those with AIDS have circulating cryptococcal antigen, indicating active infection. However, in AIDS patients in Ghana the incidence is lower; in Zambia the infection is again more common. The explanation for these fluctuations is unknown. However, clustering of cases may occur and has been seen for instance in Papua New Guinea, where the disease is mainly caused by C. neoformans var. gattii.
The common presentation of cryptococcal infection in the non-AIDS patient is meningitis, although headache and neck stiffness may not be severe; but other signs such as confusion, 11drowsiness, photophobia and cranial nerve palsies may be seen. Signs of dissemination such as papular or ulcerative skin lesions, lytic bone deposits and prostatitis may be found. In patients with AIDS, the symptoms of meningitis are often minimal and fever may be the main clinical sign, together with malaise and tiredness.51
The laboratory diagnosis of cryptococcosis is straightforward. It depends on the demonstration of the organism(s) by stained smears of CSF or sputum with Indian ink or nigrosin (Fig. 1). The capsule surrounding the organism displaces the opaque stain and the surrounding clear halo seen with the microscope is typical of Cryptococcus. The organism can be cultured readily on conventional mycological media such as Sabouraud's agar, although it may take 3–12 days for the yeasts to be recognizable. Sources of culture material include CSF, sputum and biopsies. In patients with AIDS blood cultures may also be positive.
The quickest method of diagnosis is the use of the antigen detection test, which employs antibody-sensitized latex particles or an enzyme-linked immunosorbent assay test. Both are used to detect capsular antigen in serum or CSF. The tests are specific and the latex tests will produce a positive response in 30 min. It can also be used to follow the course of therapy. Biopsy material will also show the large yeast cells using periodic acid–Schiff or Grocott stains; the mucicarmine stain is specific for cryptococcal capsule, which it stains pink.
The main therapy in the non-AIDS patient is a combination of intravenous amphotericin B (0.4–0.8 mg/kg daily) and flucytosine (120–150 mg/kg daily divided in four doses). The response in most patients is good but therapy may have to be continued for 4–6 weeks, and sometimes longer. The treatment of the AIDS case is more complex. Few treatments can produce permanent recovery and the usual strategy is to start with a period of induction therapy followed by long-term suppression to prevent relapse. At present, the best choice of drugs is still unclear. Many units will use an initial period of amphotericin (0.4–0.8 mg/kg daily), with or without flucytosine, for 2 weeks, followed by long-term daily suppressive therapy with fluconazole (200–400 mg). Fluconazole may also be used to produce remission on its own, although the dose is usually 600 mg or higher. Again, where patients are receiving antiretrovirals long-term suppressive therapy can be withdrawn after 4–6 months.
zoom view
Fig. 1: Cryptococcus neoformans in India ink preparation (40X)
Other fungi that cause CNS infection are Candida, Aspergillus and Rhizopus species. Infections by dimorphic fungi such Coccidioides immitis, Histoplasma capsulatum and Blastomyces dermatitidis are extremely rare and usually limited to North and Central America. Laboratory diagnosis is made usually by culture and antibody testing in serum and CSF.52
 
NONINFECTIVE CONDITIONS IN TROPICS
 
Stroke in Tropics
Stroke is the most common neurological emergency and third leading cause of death next to ischemic heart disease and malignancy. It is common in tropical areas, where stroke in young and puerperal venous sinus thrombosis are commonly observed. Stroke is mainly a disease of elderly and age is a well known risk factor. Its incidence is low in rural population of many tropical countries.53,54 Common causes of stroke in tropics are rheumatic heart disease, bacterial endocarditis, Takayasu disease, Moyamoya disease, syphilis, leptospirosis, acute bacterial meningitis, tuberculosis, cysticercosis. Stroke in tropical countries has distinct epidemiological and etiological features, which should alert the physicians in these areas so as to take appropriate steps to prevent stroke.
 
TOXINS AND POISONING
In tropical countries, high temperatures and humidity allow growth of both animals and plants, many of which have neurotoxic potential (Tables 4 and 5). Early symptoms are usually sensory with paraesthesiae, suprasensitivity, hyperalgesia and pain, followed later by peripheral weakness and wasting. Impairment of tendon reflexes occurs early and all sensory modalities may be variably affected. Some have associated myelopathic disturbances with spasticity and extensor plantar responses. Involvement of the autonomic nervous system with defective sweating and vasomotor disturbances commonly occurs.55
Mycotoxins: Mushrooms of genus Inocybe and Clitocybe have peripheral muscarinic effects. Panaeolus, Psilocybe and Gymnopilus have hallucinogenic properties while Amantia group has central and autonomic effects, Gyromitra produces manifestations similar to isoniazid toxicity.12
Table 4   General classification of neurotoxins
Group
Toxins
Plant
Lathyrism, konzo, cannabis, cycad
Animal
Snake, spider, scorpion, bees, lizard
Chemicals
Metals: Mercury, arsenic, fluoride, lead, thallium
Synthetic: Solvent, pesticide, industrial chemicals
Table 5   Toxicological classification of neurotoxins
Cerebral poisons
Somniferous
Opium and derivatives
Inebriant
Barbiturates, alcohols, pesticides
Deliriant
Datura, atropine, hyoscine
Psychotropic
Phenothiazine, lysergic acid diethylamide (LSD), tricyclic antidepressants, MAO inhibitors
Spinal poisons
Strychnine, gelsemium
Peripheral poisons
Hemlock, curare, botulinum
Mixed poisons with neurotoxicity
Mushroom, snake venom, scorpion, lathyrism
Lathyrism: The peas from “Lathyrus sativus” on prolonged and predominant consumption lead to gradual development of spastic paraplegia.56 Central motor conduction time to tibialis anterior in lathyrism patient is prolonged when compared with control.
All these essentially irreversible and disabling toxic disturbances of the central, autonomic and peripheral nervous systems are preventable by avoiding or limiting exposure. Health services in developing countries should provide measures so as to reduce morbidity and mortality due to poisoning, which also consequently minimizes neurological consequences of poisoning.
 
NONMULTIPLE SCLEROSIS DEMYELINATION
The spectrum of nonmultiple sclerosis (non-MS) dem-yelinating syndrome includes the following disorders:
  1. Optic neuritis: It refers to optic neuropathy caused by any process that results in inflammation, infection or demyelination of optic nerve. It is twice as common in females with annual incidence of 3.5/100000 population. MRI of optic nerve may reveal hyperintense signal on T2
  2. Cerebellitis: Acute cerebellar ataxia of childhood usually occurs in children aged one to eight years of age. Viral infection although attributed, its serological evidence is lacking in most of the cases. A number of viruses like echo, coxsackie group A and B, polio, EBV and HSV have been implicated.
  3. Guillain-Barré syndrome (GBS): It is an acute inflammatory polyradiculopathy with annual incidence of 1–2/100000 population. Besides diverse viruses such as EBV, CMV, HIV and hepatitis viruses, Campylobacter jejuni is identified as the most common bacterial pathogen associated with GBS.
  4. Brachial and lumbosacral plexopathy: These neurolgic amyotrophic syndromes are usually unilateral. Antecedent events occur in 28–83% of patients which include infection, surgery, trauma and immunization.57
 
NUTRITIONAL IMAGING MANIFESTATIONS IN CNS
Nutritional deficiency is widespread and severe in developing countries.58 The identifiable groups of nutritional disorders of nervous system are as follows: Vitamin B complex deficiency syndromes (B1, B6, B12 and folic acid deficiency). Pathological changes are described as subacute combined degeneration of spinal cord. Nicotinic acid deficiency presents clinically with diarrhea, a light-sensitive erythematous rash progressing to thickening and atrophy with glossitis, diplopia, dysarthria, myelopathy and neuropathy with psychological and behavioral changes. There are three distinct neurological syndromes of thiamine deficiency: (i) Beriberi: the salient neurological features are painful polyneuropathy with tender calves and sensitive soles, (ii) Wernicke's encephalopathy: it may be acute or insidious, with vomiting, nystagmus, diplopia, confusion, ophthalmoplegia, retinal hemorrhages, polyneuropathy, (iii) Korsakoff's psychosis: it is associated with amnesia and confabulation. Pyridoxine deficiency clinical syndrome manifests as sporadic infantile seizure, hereditary pyridoxine responsive seizure and peripheral neuropathy. Vitamin E deficiency usually follows malabsorption and presents with weakness and gait ataxia, and vitamin D deficiency manifests as osteomalacic myopathy. Two polar forms of protein energy malnutrition exists in the children of developing countries—marasmus with stunted growth, generalized wasting of protein mass and Kwashiorkor with growth failure, edema, hypoalbuminemia and fatty liver. The features of neurologic cretinism (iodine deficiency disorder) are profound mental retardation, deaf mutism, hearing loss, rigidity and bradykinesia. Other neurological disorders following vitamin deficiency are alcoholic cerebellar degeneration and amblyopia. Physicians should be aware of diverse manifestations of nutritional deficiencies to facilitate prompt and effective treatment.
 
HIRAYAMA DISEASE
Hirayama disease, also termed nonprogressive juvenile spinal muscular atrophy of the distal upper limbs, is a kind of cervical 13myelopathy related to flexion movements of the neck. The pathogenic mechanism of this disease is attributed to forward displacement of the posterior wall of the lower cervical dural canal when the neck is in flexion, which causes marked, often asymmetric, flattening of the lower cervical cord.59,60 In patients with Hirayama disease, conventional radiographic studies of the cervical spine usually show no specific abnormalities except straight alignment or scoliosis.61 Myelography can show the forward movement of the posterior dural wall when the neck is flexed.61 MR studies in neck flexion can show not only the anterior displacement of the posterior wall but also a well-enhanced crescent-shaped mass in the posterior epidural space of the lower cervical canal.62 This mass is thought to represent congestion of the posterior internal vertebral venous plexus.
 
PARAINFECTIOUS MYELITIS
There is a wide spectrum of parainfectious myelitis which is temporally related to infection. They are not due to direct injury by infection as neurological signs appear late in the course or weeks after recovery and absence of isolation of organism from neural tissue despite presence of inflammation and demyelination in histopathology. Mechanisms proposed to explain parainfectious syndromes are direct viral effect, viral mediated immune reaction and viral disruption of regulatory mechanisms of immune system. The spectrum of parainfectious myelitis includes following disorders:
 
Acute Disseminated Encephalomyelitis
It is characterized by rapid onset of neurologic signs and symptoms following viral exanthema in children. Important pathogens associated with acute disseminated encephalomyelitis (ADEM) include measles, HSV, HIV, HHV, mumps, influenza, EBV and coxsackie B virus. Neurologic signs and symptoms include paresthesia, pain, motor weakness, spasticity, lack of coordination, dysarthria and dysphagia. Pathologically there is perivascular edema in white matter with cellular infiltration. MRI on T2 axial section shows rounded hyperintense changes in cerebral white matter in patients with ADEM.63
 
Acute Transverse Myelitis
It is an acute or subacute spinal cord dysfunction characterized by paraplegia, horizontal level of sensory impairment and sphincter dysfunction in which secondary causes have been excluded. A preceding viral illness is reported in 37% of patients. It is a disease of adults and children (rare under the age of four years). Acute transverse myelitis (ATM) has been reported following smallpox, measles, mumps, influenza, echo, herpes, EBV infection, and rabies and smallpox vaccinations. Spinal MRI on T2 sequences in sagittal section shows diffuse hyperintense signal changes in cervical and thoracic spinal cord in patients with ATM.63
 
IMAGING IN EPILEPSY
Epilepsy is a major neurological disorder in the tropics. It is therefore difficult to determine what significance should be attributed to the reported relatively low prevalence in India (up to 60 per 100000 person-years).64 In developed countries age-adjusted incidence of epilepsy is 24–53 per 100000 person-years.65 Some authors report high incidence rate in developing countries of 190 per 100000 person-years.66 Certain regions of Africa and Latin America have a very high prevalence. There is a pattern toward higher prevalence of epilepsy in tropical countries as compared to Western countries.67
Cysticercosis accounts for about half the cases of epilepsy of late onset in several tropical countries. Other parasitic infections known to cause epilepsy include schistosomiasis, paragonimiasis, sparganosis, hydatid disease, toxoplasmosis, trypanosomiasis, cerebral malaria, cerebral amebiasis and Gnathostoma spinigerum. Tuberculous, pyogenic, viral and fungal infections can also cause epilepsy in acute illness and as a late sequel. Infection with HIV has influenced the epidemiology, clinical and pathological presentation of epilepsy. New-onset seizures are usual manifestations of CNS disorders in patients infected with HIV.68 In some patients the HIV infection itself may be the cause of seizure.69
 
CONCLUSION
Infections of the CNS are being increasingly recognized as a significant cause of morbidity and mortality. This chapter has briefly described an exceedingly diverse group of infectious and noninfectious illnesses that affect the CNS in the tropical countries. The outcome of such diseases largely depends on early diagnosis and aggressive therapy especially in case of acute infections but the diagnostic dilemma continues due to overlapping clinical manifestations. HIV infection and organ transplant related immunosuppression have further increased the risk with many opportunistic pathogens. It is also important to know the disease burden in a particular tropical region so as triaging of tests especially for viral pathogens can be done to rationalize the cost. Introduction of molecular methods and neuroimaging have improved the diagnosis of CNS diseases to a large extent. Comprehensive approach involving clinician (Neurologist and neurosurgeon) and laboratory personnel (microbiologist, neuropathologist and radiologist) is likely to improve the diagnosis and management.14
REFERENCES
  1. Koskiniemi M, Raintalaiho, T, Piiparinen, H, et al. Infections of the central nervous system of suspected viral origin: a collaborative from Finland. J Neurovirol. 2001;7:400–8.
  1. Glaser CA, Gilliam, S, Schnurr, D, et al. In search of encephalitis etiologies: diagnostic challenges in the California encephalitis project, 1998-2000. Clin Infect Dis. 2003;36:731–42.
  1. Peltola H, Salo, E, Saxen, H. Incidence of Haemophilus influenzae type b meningitis in during last 18 years of vaccine use: observational study using routine hospital data. BMJ. 2005;330:18–9.
  1. Garg RK. Classic diseases revisited: Tuberculosis of the central nervous system. Postgrad Med J. 1999;75;133–40.
  1. Rock RB, Olin, M, Baker, CA, Molitor, TW, Peterson, PK. Central nervous system tuberculosis: pathogenesis and clinical aspects. Clin Microbiol Rev. 2008;21:243–61.
  1. Thwaites GE, Tran, TH. Tuberculous meningitis: many questions, too few answers. Lancet Neurol. 2005;4:160–70.
  1. Verdon R, Chevret, S, Liassy, JP, Wolff, M. Tuberculous meningitis in adults: review of 48 cases. Clin Infect Dis. 1996;22:982–8.
  1. Katti MK. Pathogenesis, diagnosis, treatment and outcome aspects of cerebral tuberculosis. Med Sci Monit. 2004;10:RA 215–29.
  1. Pappas G, Papadimitrou, P, Akritidis, N, et al. The new global map of human brucellosis. Lancet Infect Dis. 2006;6:91–9.
  1. Panicker JN, Mammachan, R, Jayakumar, RV. Primary neuroleptospirosis. Postgrad Med J. 2001;77:589–90.
  1. Azad AF, Radulovic S. Pathogenic rickettsiae as bioterrorism agents. Ann NY Acad Sci. 2003;990:1–5.
  1. Osenbach RK, Loftus, CM. Diagnosis and management of brain abscess. Neurosurg Clin N Am. 1992;3:403–20.
  1. Prasad KN, Mishra, AM, Gupta, D, Husain, N, Husain, M, Gupta, RK. Analysis of microbial etiology and mortality in patients with brain abscess. J Infection. 2006;53:221–7.
  1. Gupta RK, Vatsal, DK, Hussain, N, et al. Differentiation of tuber-culous from pyogenic brain abscess with in vivo proton MR spectroscopy and magnetization transfer. Am J Neuroradiol. 2001;22:1503–9.
  1. Luthra G, Parihar, A, Nath, K, et al. Comparative evaluation of fungal, tubercular and pyogenic brain abscesses with convention, diffusion MR imaging and proton MR spectroscopy. Am J Neuroradiol. 2007;28:132–8.
  1. Kupila L, Vuorinem, T, Vainionpaa, R, Hukkanen, V, Marttila, RJ, Kotilainen, P. Etiology of aseptic meningitis and encephalitis in an adult population. Neurology. 2006;66:75–80.
  1. Yu Y. Phenotypic and genotypic characteristics of Japanese encephalitis attenuated live vaccine virus SA-14-14-2 and their stabilities. Vaccine 2010; PMID: 20226891 (Epub ahead of print).
  1. Jeffery KJ, Read, SJ, Peto, TE, et al. Diagnosis of viral infections of the central nervous system: clinical interpretation of PCR results. Lancet. 1997;349: 13.
  1. Katz SL. Polio-new challenges in 2006. J Clin Virol. 2006;36: 163–5.
  1. Huang QS, Greening, G, Baker, MG, et al. Persistence of oral polio vaccine virus after its removal from the immunisation schedule in New Zealand. Lancet. 2005;366:394–6.
  1. Han MH, Walker, M, Zunt, JR. Neurological infections in the returning international traveler. Infect Dis. Am Acad Neurol Continuum. 2006;12:133–58.
  1. Nath A, Sacktor N. Influence of highly active antiretroviral therapy on persistence of HIV in the central nervous system. Curr Opin Neurol. 2006;19:358–61.
  1. Proietti FA, Carneiro-Proietti AB, Catalan-Soares BC, et al. Global epidemiology of HTLV-1 infection and associated diseases. Oncogene. 2005;24:6058–68.
  1. Grindstaff P, Gruener G. The peripheral nervous system complications of HTLV-1 myelopathy (HAM/TSP) syndromes. Semin Neurol. 2005;25:315–27.
  1. Kennedy PG. Diagnostic and neuropathogenesis issues in human African trypanosomiasis. Int J Parasitol. 2006;36:505–12.
  1. Oliveira-Filho J, Viana, LC, Vieira-de-Melo RM, et al. Chagas disease is an independent risk factor for stroke: baseline characteristics of a Chagas Disease cohort. Stroke. 2005;36: 2015–17.
  1. Visvesvara GS, Moura, H, Schuster, FL. Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS Immunol Med Microbiol. 2007: 50;1–16.
  1. Gelman BB, Popov, V, Chaljub, G, et al. Neuropathological and ultrastructural features of amebic encephalitis caused by Sappinia diploidea. J Neuropathol Exp Neurol. 2003;62:990–8.
  1. Vastava PB, Pradhan, S, Jha, S, Prasad, KN, Kumar, S, Gupta, RK. MRI features of toxoplasma encephalitis in the immunocompetent host: a report of two cases. Neuroradiology. 2002;44:834–8.
  1. Walker M, Kublin, JG, Zunt, JR. Parasitic central nervous system infections in immunocompromised hosts: malaria, microsporidiosis, leishmaniasis, and African trypanosomiasis. Clin Infect Dis. 2006;42:115–25.
  1. Prasad KN, Prasad, A, Gupta, RK, et al. Neurocysticercosis in patients with Active epilepsy from Pig Farming Community of Lucknow District, North India. Trans Roy Soc Trop Med Hyg. 2009;103:144–50.
  1. Prasad A, Gupta, RK, Nath, K, et al. What Triggers Seizures in Neurocysticercosis? A MRI Based Study in Pig Farming Community from a District of North India. Parasitol Int. 2008;57: 166–71.
  1. Prasad A, Prasad, KN, Gupta, RK, Pradhan, S. Increased expression of ICAM-1 among symptomatic neuorocysticercosis. J Neuroimmunol. 2009;206:118–20.
  1. Prasad KN, Prasad, A, Verma, A, Singh, AK. Human cysticercosis and Indian scenario: A Review. J Biosciences. 2008;33:571–82.
  1. Takayanagui OM, Odashimba, NS. Clinical aspects of neuro-cysticercosis. Parasitol Int. 2006; 55:S111–S115
  1. Del Brutto OH, Rajshekhar V, White AC. Jr, et al. Proposed diagnostic criteria for neurocysticercosis. Neurology. 2001;57: 177–83
  1. Garcia HH, Del Brutto OH, Nash TE, Whit Jr C, Tsang VC, Gilman RH. New concepts in the diagnosis and management of neurocysticercosis (Taenia solium). Am J Trop Med Hyg. 2005;72:3–9.
  1. Verma A, Prasad, KN, Singh, AK, Nyati, KK, Gupta, RK, Paliwal, VK. Evaulation of the MTT lymphocyte proliferation assay for the diagnosis of neurocysticercosis. J Microbiol Methods 2010 (in press).15
  1. Almedia CR, Ojopi, EP, Nunes, CM, et al. Taenia solium DNA is present in the cerebrospinal fluid of neurocysticercosis patients and can be used for diagnosis. Eur Arch Psychiatry Clin Neurosci. 2006;256:307–10.
  1. Boatin BA, Richard Jr O. Control of onchocerciasis. Adv Parasitol. 2006;61:349–94.
  1. Kaiser C, Asaba, G, Kasoro, S, et al. Mortality from epilepsy in an onchocerciasis-endemic area in West Uganda. Trans R Soc Trop Med Hyg. 2007;101:48–55.
  1. Clement-Rigolet MC, Danis, M, Caumes, E. Gnathostomiasis, an exotic disease increasingly imported into Western countries. Presse Med. 2004;33:1527–32.
  1. Schmutzhard E, Boongird, P, Vejjajiva, A. Eosinophilic meningitis and radiculomyelitis in Thailand caused by CNS invasion of Gnasthostoma spinigerum and Angiostrongylus cantonensis. J Neurol Neurosurg Psychiatry. 1988;51:80–8.
  1. Lawn SD, Wilkinson, RJ. Immune reconstitution disease associated with parasitic infections following antiretroviral treatment. Parasite Immunol. 2006;28:625–33.
  1. Rumana M, Mahadevan, A, Nayl Khurshid M, et al. Cestode parasitic infestation: intracranial and spinal hydatid disease-a clinico-pathological study of 29 cases from South India. Clin Neuropathol. 2006;25:98–104.
  1. Gryceels B, Palman, K, Clerinx, J, et al. Human schistosomiasis. Lancet. 2006;368:1106–18.
  1. Betting LE, Piran Jr, de Souza Queiroz L, et al. Seizures and cerebral schistosomiasis. Arch Neurol. 2005;62:1008–10.
  1. Turk M, Kaptan, F, Turker, N, et al. Clinical and laboratory aspects of a trichinellosis outbreak in Izmir, Turkey. Parasite. 2006;13: 65–70.
  1. Gelal F, Kumral, E, Vidini, BD, et al. Diffusion-weighted and conventional MRI imaging in neurotrichinosis. Acta Radiol. 2005;46:196–9.
  1. Zhang JS, Huan, Y, Sun, LJ, et al. MRI features of pediatric cerebral paragonimiasis in the active stage. J Magn Reson Imaging. 2006;23:569–73.
  1. Perfect JR, Cox, GM. Cryptococcosis. In: Merz W, Hay RJ. (Eds). Medical Mycology. Topley and Wilsons Microbiology and Microbial Infections. Edward Arnold.  London:  2005;(5): 637–58.
  1. Thomson RB Jr, Bertram H. Laboratory diagnosis of central nervous system infections. Infect Dis Clin North Am. 2001;15: 1047–71.
  1. Osuntokun BO. Stroke in the Africans. Afr J Med Sci. 1977;6:39–53.
  1. Calndre L, Ortega, JF, Bermejo, F. Anticoagulation and hemorrhagic fraction in cerebral embolism secondary to rheumatic heart disease. Arch Neurol. 1984;41:1152–4.
  1. Misra UK, Kalita J. Environmental neurotoxins in the tropics. In: Misra UK, Kalita J (Eds). Tropical Neurology. Georgetown: Landes Bioscience;  2003. pp. 344–69.
  1. Misra UK, Sharma, VP. Peripheral and central conduction studies in neurolathyrism. J Neurol Neurosurg Psychiat. 1994;57:572–7.
  1. Kalita J, Misra, UK. Parainfectious demyelinating diseases of the nervous system. In: Misra UK, Kalita J. (Eds). Tropical Neurology, Landes Bioscience;  Georgetown:  2003. pp. 217–37.
  1. Wadia NH, Misra, UK, Kalita, J. Nutritional deficiency disorders of the nervous system. In: Misra UK, Kalita J, Shakir RA. (Eds). Tropical Neurology. Landes Bioscience;  Austin:  2003. pp. 470–90.
  1. Hirayama K. Non-progressive juvenile spinal muscular atrophy of the distal upper limb (Hirayama's disease). In: De Jong JMBV (Ed). Handbook of Clinical Neurology. Elsevier;  Amsterdam,  the Netherlands: 1991. pp. 107–20.
  1. Hirayama K, Toyokura, Y, Tsubaki, T. Juvenile muscular atrophy of unilateral upper extremity: A new clinical entity. Psychiatr Neurol Jpn. 1959;61:2190–97.
  1. Mukai E, Sobue, I, Muto, T, Takahashi, A, Goto, S. Abnormal radiological findings on juvenile-type distal and segmental muscular atrophy of upper extremities. Clin Neurol (Tokyo). 1985;25:620–6.
  1. Mukai E, Matsuo, T, Muto, T, Takahashi, A, Sobue, I. Magnetic resonance imaging of juvenile-type distal and segmental muscular atrophy of upper extremities. Clin Neurol (Tokyo). 1987;27:99–107.
  1. Kalita J, Misra, UK. Parainfectious demyelinating diseases of the nervous system. In: Misra UK, Kalita J, Shakir RA. (Eds). Tropical Neurology. Landes Bioscience;  Austin:  2003. pp. 217–37.
  1. Sawhney IM, Singh, A, Kaur, P, et al. A case control study and one year follow-up of registered epilepsy cases in a resettlement colony of North India, a developing tropical country. J Neurol Sci. 1999;165:31–5.
  1. Jallon P. Epilepsy and epileptic disorders, an epidemiological marker? Contribution of descriptive epidemiology. Epileptic Disord. 2002;4:1–13.
  1. Scott RA, Lhatoo, SD, Sander JWAS. The treatment of epilepsy in developing countries: where do we go from here? Bull World Health Organ. 2001;79:344–51.
  1. Preux PM, Druet-Cabanac M. Epidemiology of epilepsy in sub-Saharan Africa. Lancet Neurol. 2005;4:21–31.
  1. Bhigjee AI. Seizures in HIV/AIDS: a southern African perspective. Acta Neurol Scand Suppl. 2005;181:8–11.
  1. Mullin P, Green, G, Bakshi, R. Special population: the management of seizures in HIV-positive patients. Curr Neurol Neurosci Rep. 2004;4:308–14.