Post-malaria neurological syndrome: four cases, review of the literature and clarification of the nosological framework

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proguanil 3 infectiousdiseasesdrugs
atovaquone 3 infectiousdiseasesdrugs
cysticercosis 1 infectiousdiseases
dengue fever 1 infectiousdiseases
mixed malaria 1 infectiousdiseases
yellow fever 1 infectiousdiseases
Rift Valley fever 2 infectiousdiseases
infectious disease 2 infectiousdiseases
malaria 62 infectiousdiseases
meningitis 7 infectiousdiseases
cerebral malaria 3 infectiousdiseases
toxocariasis 1 infectiousdiseases
trypanosomiasis 2 infectiousdiseases
cefotaxime 1 infectiousdiseasesdrugs
ceftriaxone 1 infectiousdiseasesdrugs
doxycycline 1 infectiousdiseasesdrugs
quinine 4 infectiousdiseasesdrugs

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atovaquone 10376 criteria. The treatment regimen included intravenous artesunate (2.4 mg/kg, 5 doses for 3 days) then atovaquone /proguanil (1000/400 mg per day for 3 days), and the patient improved quickly, both clinically and
atovaquone 15159 falciparum malaria without severity criteria in July 2013. That episode was treated with a 3-day course of atovaquone /proguanil (standard treatment). The patient experienced a second symptomatic episode with a positive
atovaquone 17458 with non-severe (2% parasitaemia) falciparum malaria on 28 November and treated with a 3-day course of atovaquone /proguanil with good outcome. Thirteen days later (day 15) she became confused, aphasic and anosognosic.
cefotaxime 11314 titre of anti-nuclear factor (1/80) with no positivity for anti-DNA. Thereafter, he was treated with cefotaxime and acyclovir from day 12–21 (until a second CSF analysis showed no viral or bacterial infection),
ceftriaxone 10825 confusion, ataxia, tremor, and dysarthria, and his fever increased to 39 °C. On day 11, he was given ceftriaxone for presumed enteric fever. On day 12, he remained confused and started having visual hallucinations
doxycycline 1531 treated with quinine in 60%, mefloquine in 46%, artemisinin derivatives in 41%, antifolic drugs in 30%, doxycycline in 8% and other types in 8%. The mean symptom-free period was 15 days. PMNS signs were confusion (72%),
proguanil 10387 treatment regimen included intravenous artesunate (2.4 mg/kg, 5 doses for 3 days) then atovaquone/ proguanil (1000/400 mg per day for 3 days), and the patient improved quickly, both clinically and biologically
proguanil 15170 without severity criteria in July 2013. That episode was treated with a 3-day course of atovaquone/ proguanil (standard treatment). The patient experienced a second symptomatic episode with a positive blood smear
proguanil 17469 non-severe (2% parasitaemia) falciparum malaria on 28 November and treated with a 3-day course of atovaquone/ proguanil with good outcome. Thirteen days later (day 15) she became confused, aphasic and anosognosic. CSF analysis
quinine 1440 were men. Malaria was severe in 85% of cases, showed neurological involvement in 53%, and treated with quinine in 60%, mefloquine in 46%, artemisinin derivatives in 41%, antifolic drugs in 30%, doxycycline in 8%
quinine 15463 with good outcome. He then consulted on day 37 for vomiting and a 40 °C fever for which intravenous quinine was initiated despite a negative blood smear. On day 38, he presented convulsions and a severe alteration
quinine 18603 parasitaemia) in July 1999 after a trip to Ivory Coast. She was initially treated with intravenous quinine (25 mg/kg/day) and on day 5 was given an oral dose of quinine (500 mg tid) after which she developed
quinine 18666 was initially treated with intravenous quinine (25 mg/kg/day) and on day 5 was given an oral dose of quinine (500 mg tid) after which she developed hypoacusis. On day 6, she was treated with mefloquine (6 × 250 mg
Select Disease Character Offset Disease Term Instance
Rift Valley fever 16380 were negative or normal: HSV, EBV, VZV, HIV, VHB, VHC, HHV6, adenovirus, dengue fever, Chikungunya, Rift Valley fever virus, West-Nile virus, Borrelia, Coxiella, Brucella, Bartonella, Tropheryma whipplei, gram-negative
Rift Valley fever 17812 investigations were all negative (including HSV, VZV and enterovirus, HIV, Chikungunya, dengue, West Nile and Rift Valley fever s, yellow fever and African trypanosomiasis). Intravenous acyclovir was stopped after 2 days following
cerebral malaria 2916 429,000 deaths in 2015 [[1]]. The disease causes neurological impairment during its acute phase and cerebral malaria can provoke neurological sequelae. Additionally, a return of neurological signs after cure has been
cerebral malaria 21984 (determined on 46 published cases)Mean age33 yearsSex ratio (% male)66%Previous severe malaria85%Previous cerebral malaria 50%Malaria speciesPlasmodium falciparum (also P. vivaxa)Previous treatment for malariaNo effectTraveler
cerebral malaria 23028 population, PMNS developed mostly in adults (mean age of 33) after severe falciparum malaria (85%), with cerebral malaria in 50% of the cases. It was seen most frequently in people who live in (two-thirds of reported cases),
cysticercosis 16544 Brucella, Bartonella, Tropheryma whipplei, gram-negative bacilli, TPHA-VDRL, African trypanosomiasis, cysticercosis , toxocariasis, anti-nuclear factor (ANF), anti-neutrophil cytoplasmic antibodies (ANCA), complement,
dengue fever 16353 (tests for all of the following were negative or normal: HSV, EBV, VZV, HIV, VHB, VHC, HHV6, adenovirus, dengue fever , Chikungunya, Rift Valley fever virus, West-Nile virus, Borrelia, Coxiella, Brucella, Bartonella, Tropheryma
infectious disease 694 literature performed to clarify the nosological framework of this syndrome.MethodsA French teaching hospital infectious disease s database was investigated for all PMNS cases occurring between 1999 and 2016 and the PubMed database
infectious disease 25382 DCA as they share the same prognosis and outcome [[4], [19]].PMNS shares many features with CNS post- infectious disease s such as ADEM and auto-immune encephalitis. ADEM [[32]–[37]] is a rare, acute, post-infectious (bacterial
malaria 27 Title: Malaria JournalPost- malaria neurological syndrome: four cases, review of the literature and clarification of the nosological frameworkYanis
malaria 360 10/2018Publication date (pmc-release): 10/2018Publication date (collection): /2018AbstractBackgroundPost- malaria neurological syndrome (PMNS) is a debated entity, defined by neurological complications following a
malaria 473 neurological syndrome (PMNS) is a debated entity, defined by neurological complications following a post- malaria symptom-free period and a negative blood smear. Four cases of PMNS are hereby reported and a review
malaria 952 institutions after 1997. A case was defined by the de novo appearance of neurological signs following a post- malaria symptom-free period, a negative blood smear, and no bacterial or viral differential diagnoses.ResultsFour
malaria 1269 found matching the definition. In the institution, the estimated PMNS incidence rate was 1.7 per 1000 malaria cases overall. Of the 52 patients (mean age 33 years), 65% were men. Malaria was severe in 85% of cases,
malaria 2288 17.4 days.ConclusionPMNS is a rare entity englobing neurological signs after severe or non-severe malaria . It appears after a symptom-free period. PMNS occurred following treatment of malaria with a wide range
malaria 2374 or non-severe malaria. It appears after a symptom-free period. PMNS occurred following treatment of malaria with a wide range of anti-malarials. The disease is self-limiting and associated with good outcome.
malaria 2408 after a symptom-free period. PMNS occurred following treatment of malaria with a wide range of anti- malaria ls. The disease is self-limiting and associated with good outcome. MRI patterns underline a possible
malaria 2717 falciparum and Plasmodium vivax should be added to the list of pathogens causing ADEM.BackgroundFalciparum malaria remains a common cause of morbidity and mortality, with an estimated 212 million cases and 429,000 deaths
malaria 2925 deaths in 2015 [[1]]. The disease causes neurological impairment during its acute phase and cerebral malaria can provoke neurological sequelae. Additionally, a return of neurological signs after cure has been
malaria 3392 self-limiting, delayed cerebellar ataxia (DCA) syndrome 3–41 days after the onset of fever due to falciparum malaria . However, it was difficult to establish a clear relationship with a post-malaria phenomenon as the onset
malaria 3473 due to falciparum malaria. However, it was difficult to establish a clear relationship with a post- malaria phenomenon as the onset of neurological signs occurred while almost half (34/74) of the patients still
malaria 3652 half (34/74) of the patients still had positive blood smears, and 11 of them had not received any anti- malaria l treatment.In 1997, Nguyen et al. [[4]] provided a first definition of post-malaria neurological syndrome
malaria 3736 received any anti-malarial treatment.In 1997, Nguyen et al. [[4]] provided a first definition of post- malaria neurological syndrome (PMNS) in a report on 22 Vietnamese patients who presented encephalitic signs
malaria 3901 patients who presented encephalitic signs after a symptom-free period (median time of 96 h) after malaria cure, and additionally had negative blood smears for Plasmodium falciparum and negative etiological
malaria 4074 falciparum and negative etiological investigations. In their study, the use of mefloquine for severe malaria was associated with PMNS (relative risk 7.4). Since then, a number of case reports and series have been
malaria 4897 with the goal of contributing to a better understanding of this rare entity.MethodsCase definition of malaria Malaria was defined as the association of compatible clinical signs with a positive blood smear and/or
malaria 5076 a positive blood smear and/or antigens for a Plasmodium spp. The disease of patients with imported malaria in France were classified as severe or non-severe using the French 2007 classification [[5]].Case definition
malaria 5309 defined as the occurrence of de novo neurological signs after a symptom-free period following acute malaria (whatever the Plasmodium species, i.e., P. falciparum Plasmodium vivax, Plasmodium ovale, Plasmodium
malaria 5418 (whatever the Plasmodium species, i.e., P. falciparum Plasmodium vivax, Plasmodium ovale, Plasmodium malaria e or Plasmodium knowlesi), associated with a negative blood smear and no retainable differential diagnosis.
malaria 5765 between 1999 and 2016 were included. PubMed was also investigated for neurological conditions following malaria using the following Mesh terms date-limited to ≥ 1997: “post-malaria neurological syndrome”,
malaria 5840 neurological conditions following malaria using the following Mesh terms date-limited to ≥ 1997: “post- malaria neurological syndrome”, “post-malaria and ADEM”, “Plasmodium/falciparum/vivax/ovale/malariae/knowlesi”
malaria 5882 following Mesh terms date-limited to ≥ 1997: “post-malaria neurological syndrome”, “post- malaria and ADEM”, “Plasmodium/falciparum/vivax/ovale/malariae/knowlesi” and “neurological” and “encephalitis”
malaria 5940 “post-malaria neurological syndrome”, “post-malaria and ADEM”, “Plasmodium/falciparum/vivax/ovale/ malaria e/knowlesi” and “neurological” and “encephalitis” and “ADEM” and “cerebellar”.In the
malaria 6186 (hospital patients plus those screened from the literature), the following data was assessed: age, gender, malaria severity, malaria treatment, symptom-free period duration, fever presence, neurological signs (confusion,
malaria 6204 those screened from the literature), the following data was assessed: age, gender, malaria severity, malaria treatment, symptom-free period duration, fever presence, neurological signs (confusion, cerebellar and
malaria 7078 Windows. Analysis was restricted to the P. falciparum group.ResultsFour cases of PMNS after imported malaria (Table 1)Four of 2314 patients treated in the hospital for imported malaria during the study period
malaria 7155 of PMNS after imported malaria (Table 1)Four of 2314 patients treated in the hospital for imported malaria during the study period fit the case definition of PMNS. Therefore, the estimated PMNS incidence rate
malaria 7299 definition of PMNS. Therefore, the estimated PMNS incidence rate for the hospital was 1.7 per 1000 malaria cases overall (95% CI 0.7–4.0 per 1000).Table 1Main clinical characteristics for cases of post-malaria
malaria 7405 malaria cases overall (95% CI 0.7–4.0 per 1000).Table 1Main clinical characteristics for cases of post- malaria neurological syndrome following P. falciparum (A), P. vivax (B) and mixed (C) infectionsNAgeGenderCerebral
malaria 7520 neurological syndrome following P. falciparum (A), P. vivax (B) and mixed (C) infectionsNAgeGenderCerebral malaria Severe malariaTreatment of malariaSymptom-free period (days)FeverConfusionSeizuresPsychosisCerebellar
malaria 7534 following P. falciparum (A), P. vivax (B) and mixed (C) infectionsNAgeGenderCerebral malariaSevere malaria Treatment of malariaSymptom-free period (days)FeverConfusionSeizuresPsychosisCerebellar involvementMotor
malaria 7554 falciparum (A), P. vivax (B) and mixed (C) infectionsNAgeGenderCerebral malariaSevere malariaTreatment of malaria Symptom-free period (days)FeverConfusionSeizuresPsychosisCerebellar involvementMotor deficitA—PMNS
malaria 10006 presented with fever, headaches and vomiting, and thereafter received treatment in Paris for severe malaria (positive thick drop for P. falciparum with 5 parasites/2 μL, positive HRP2 antigen test) with hepatic
malaria 15063 29-year-old Caucasian male who worked in Ivory Coast. He presented a first episode of acute falciparum malaria without severity criteria in July 2013. That episode was treated with a 3-day course of atovaquone/proguanil
malaria 15671 alteration of consciousness requiring sedation and ventilation. He was evacuated to Paris where his anti- malaria l treatment was changed to artesunate despite a still negative blood smear. On day 42, sedation was stopped
malaria 15939 generalized convulsions and consequently had to be re-sedated. The blood test was again negative for malaria but an HRP2 antigen test was positive. T2 and T1 gadolinium-enhanced MRI sequences on day 48 showed
malaria 17400 vomiting and on the 18th returned to Paris. She was diagnosed with non-severe (2% parasitaemia) falciparum malaria on 28 November and treated with a 3-day course of atovaquone/proguanil with good outcome. Thirteen days
malaria 18490 recovered on day 87.Case 4 was a 43-year-old Caucasian female who presented with severe falciparum malaria (4.5% parasitaemia) in July 1999 after a trip to Ivory Coast. She was initially treated with intravenous
malaria 19755 vivax together. Of these 48 patients, 16 were travellers (15 P. falciparum and 1 P. vivax) who acquired malaria while abroad and 32 were inhabitants of countries endemic for the infection (27 P. falciparum and 5
malaria 19916 endemic for the infection (27 P. falciparum and 5 P. vivax). No cases were described with P. ovale, P. malaria e or P. knowlesi.Matching the results of the local cases and those of the literatureThe main clinical
malaria 20154 Table 1. Four patients presented PMNS after P. vivax infection alone [[23]–[26]] and 2 after mixed malaria infections [[27], [28]]. Three were children, all after P. vivax infection [[23], [24], [26]]. One PMNS
malaria 21965 PMNS features (determined on 46 published cases)Mean age33 yearsSex ratio (% male)66%Previous severe malaria 85%Previous cerebral malaria50%Malaria speciesPlasmodium falciparum (also P. vivaxa)Previous treatment
malaria 21993 46 published cases)Mean age33 yearsSex ratio (% male)66%Previous severe malaria85%Previous cerebral malaria 50%Malaria speciesPlasmodium falciparum (also P. vivaxa)Previous treatment for malariaNo effectTraveler
malaria 22079 malaria85%Previous cerebral malaria50%Malaria speciesPlasmodium falciparum (also P. vivaxa)Previous treatment for malaria No effectTraveler or local populationDescribed in both populationsSymptom-free period since malaria (mean)15 daysFever46%Mental
malaria 22178 malariaNo effectTraveler or local populationDescribed in both populationsSymptom-free period since malaria (mean)15 daysFever46%Mental confusion72%Seizures35%Psychosis26%Cerebellar disorders28%Motor deficit13%MRI
malaria 23008 studied patient population, PMNS developed mostly in adults (mean age of 33) after severe falciparum malaria (85%), with cerebral malaria in 50% of the cases. It was seen most frequently in people who live in
malaria 23037 PMNS developed mostly in adults (mean age of 33) after severe falciparum malaria (85%), with cerebral malaria in 50% of the cases. It was seen most frequently in people who live in (two-thirds of reported cases),
malaria 23181 most frequently in people who live in (two-thirds of reported cases), but also in those who travel to, malaria -endemic areas. PMNS was also seen after vivax malaria, notably in children in 50% of the cases [[23],
malaria 23235 reported cases), but also in those who travel to, malaria-endemic areas. PMNS was also seen after vivax malaria , notably in children in 50% of the cases [[23], [24], [26]]. There was a mean symptom-free period of
malaria 24353 encephalopathy.A study from Vietnam had concluded that mefloquine was a risk factor for PMNS after severe malaria (relative risk of 7.4; 95% CI 2.5–22) [[4]]. However, only 3 of the 19 patients published after that
malaria 24916 association or causative effect for mefloquine and PMNS.Cerebellar signs can be seen not only in severe malaria , where they respond to anti-malarial treatment [[29]–[31]], but also in PMNS, where the inefficacy
malaria 24952 mefloquine and PMNS.Cerebellar signs can be seen not only in severe malaria, where they respond to anti- malaria l treatment [[29]–[31]], but also in PMNS, where the inefficacy of anti-malarials and the absence of
malaria 25033 they respond to anti-malarial treatment [[29]–[31]], but also in PMNS, where the inefficacy of anti- malaria ls and the absence of parasites argue for a different, perhaps immune, mechanism. Overall, 30% of the
malaria 27446 3 months after HSV encephalitis [[43]]. No neuronal auto-antibodies have been found to be related with malaria but new auto-antigens are being discovered at a pace of about one per year [[35]]. In AIE as in PMNS,
malaria 28918 demonstration of that has been made to date. The authors of the only study on inflammatory pathways of malaria l post infectious neurological complications reported increased blood and CSF pro-inflammatory cytokines,
malaria 29585 to cytoadherence; this is the case even after P. falciparum clearance and even in non-neurological malaria [[47]]. The fact that cytoadherence is less significant, or at least less frequent, [[48], [49]] in
malaria 30390 probably due to various pathophysiological mechanisms (Fig. 2).Fig. 2Nosological framework for post- malaria neurological syndrome. DCA is difficult to classify in PMNS because in most of the published cases,
malaria 30597 data on parasite clearance was lacking. However, other elements (delay, lack of sensitivity to anti malaria ls) advocate for at least a relationship between them. Delayed post-infectious cerebellar involvement
malaria 30960 MRI magnetic resonance imaging, DCA diffuse cerebellar ataxia, AIE autoimmune encephalitis, PMNS post- malaria neurological syndromeThe use of steroids in PMNS is another topic worth discussing. According to the
malaria 32229 exchange discussed.ConclusionPMNS is a rare entity englobing a range of neurological disorders following malaria cure. There appears to be no direct role for the parasite but rather a putative immune-mediated aggression
malaria 32473 characteristics can fit into the diagnosis of post-infectious encephalitis, ADEM or AIE. The addition of malaria due to P. falciparum and P. vivax parasites to the list of pathogens causing ADEM should be highly considered.
meningitis 1846 (13%). Cerebrospinal fluid analyses showed high protein levels in 77% (mean 1.88 g/L) and lymphocytic meningitis in 59.5% (mean 48 WBC/mm3) of cases. Electroencephalograms were pathological in 93% (14/15) of cases,
meningitis 10994 confused and started having visual hallucinations and urine incontinence. CSF analysis showed lymphocytic meningitis (Table 2), MRI was normal and EEG revealed asymmetric (right) frontal slowing. Laboratory results showed
meningitis 16128 sequences on day 48 showed hippocampal lesions (Fig. 1), EEG diffuse slowing, and CSF analysis lymphocytic meningitis (Table 2a). Differential diagnoses such as infectious or inflammatory/immunological diseases were ruled
meningitis 17605 Thirteen days later (day 15) she became confused, aphasic and anosognosic. CSF analysis showed lymphocytic meningitis (Table 2). EEG showed frontal bilateral slowing and MRI no abnormalities. Infectious investigations
meningitis 20486 findings. In the P. falciparum group, of the 42 CSF analyses available, 25 (60%) showed lymphocytic meningitis (mean of 48 cells/mm3), and 33 (78%) high protein levels (mean of 1.4 g/L) without low glucose levels.
meningitis 22353 confusion72%Seizures35%Psychosis26%Cerebellar disorders28%Motor deficit13%MRI (abnormal)43% mostly white matter lesionsCSF52% lymphocytic meningitis , 77% high protein level but normal glucose levelEEG (abnormal)94% (encephalopathy)TreatmentCorticosteroids
meningitis 23766 analyses were pathological in 60% of cases, showing high protein levels (1.4 g/L), and lymphocytic meningitis (96% lymphocytes). White matter abnormalities were always present in abnormal (43% of the cases) MRI
mixed malaria 20148 in Table 1. Four patients presented PMNS after P. vivax infection alone [[23]–[26]] and 2 after mixed malaria infections [[27], [28]]. Three were children, all after P. vivax infection [[23], [24], [26]]. One PMNS
toxocariasis 16559 Bartonella, Tropheryma whipplei, gram-negative bacilli, TPHA-VDRL, African trypanosomiasis, cysticercosis, toxocariasis , anti-nuclear factor (ANF), anti-neutrophil cytoplasmic antibodies (ANCA), complement, anti-phospholipid
trypanosomiasis 16527 Borrelia, Coxiella, Brucella, Bartonella, Tropheryma whipplei, gram-negative bacilli, TPHA-VDRL, African trypanosomiasis , cysticercosis, toxocariasis, anti-nuclear factor (ANF), anti-neutrophil cytoplasmic antibodies (ANCA),
trypanosomiasis 17857 and enterovirus, HIV, Chikungunya, dengue, West Nile and Rift Valley fevers, yellow fever and African trypanosomiasis ). Intravenous acyclovir was stopped after 2 days following the negative result for HSV PCR in CSF.
yellow fever 17832 negative (including HSV, VZV and enterovirus, HIV, Chikungunya, dengue, West Nile and Rift Valley fevers, yellow fever and African trypanosomiasis). Intravenous acyclovir was stopped after 2 days following the negative

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