Uncommon neurological manifestations of a common tropical vector borne disease.

Malaria poses a major public health problem in India, where it is endemic, especially severe malaria caused by Plasmodium falciparum infestation. There have been great changes in the clinical manifestation of severe falciparum malaria over the past couple of decades, with a shift from cerebral malaria to fever with jaundice, renal failure, bleeding diathesis, and multi-organ dysfunction syndrome. Here, we discuss two cases of severe falciparum malaria which presented with extremely uncommon neurological manifestations.

INTRODUCTION

Falciparum malaria is particularly prone to a complicated clinical course. The last two decades have shown great changes in the manifestations of severe falciparum malaria, with a shift from cerebral malaria to fever with jaundice, renal failure, bleeding diathesis, and multi-organ dysfunction syndrome.[1] The current publications of the Government of India with reference to malaria show that jaundice has become very common, along with anemia and renal failure.[1] We describe two unusual cases of falciparum malaria in patients who initially presented with more common clinical manifestations, but the course evolved into altogether very uncommon neurological manifestation.

CASE REPORTS

Case 1

A 62-year-old male patient was admitted with after the onset of fever with chills and rigor lasting for 5 days. The sensorium was reportedly altered since the day before admission. He had no headache, vomiting, jaundice, seizure or any weakness. He was neither diabetic nor hypertensive. There was no history of any other recent illness or vaccination.

Physical examination revealed that he was febrile (103°F), tachycardic (pulse rate – 124/min), normotensive (blood pressure [BP] – 110/70), and tachypneic (respiratory rate – 36/min). Neurologic examination showed drowsiness without any focal neurological deficit or meningeal signs. Plantar response was extensor bilaterally. Clinical examinations of respiratory, cardiovascular, and abdominal systems revealed no abnormality.

Full blood count revealed a normocytic anemia (hemoglobin – 10.4 g/dl, mean corpuscular volume – 82 fl), and erythrocytic sedimentation rate (ESR) was 38 mm in 1sth (Westergren method). Thick and thin blood smears were prepared which showed ring forms of Plasmodium falciparum and immunochromatographic test for P. falciparum histidine-rich protein 2 (PfHRP-2)-based assay (ICT, Access Bio. Inc., NJ, USA) was strongly positive. Blood tests revealed impaired renal functions (serum urea – 85 mg/dl and serum creatinine – 2.4 mg/dl), whereas liver function tests (LFTs) and electrolytes were normal. Hence, a diagnosis of severe falciparum malaria with cerebral manifestations and renal failure was made and a treatment with intravenous artesunate was initiated at the dose of 2.4 mg/kg at 0, 12, and 24 h, then once daily. He also underwent hemodialysis once and started improving on the 3rd day. A clear clinical improvement was shown upon treatment, until he became fully conscious and ambulant on day 4.

On day 5 (10 days after the onset of fever), he developed weakness of lower limbs first and then upper limbs, which progressively worsened over the next 3 days, making the patient bed-ridden eventually. Neurologic examination was performed. Higher functions were maintained; cranial nerve functions were intact; a lower motor type of quadriparesis was shown. Muscle strength was reduced to 2/5 in lower limbs and 3/5 in upper limbs. There was hypotonia, but no fasciculations were detected. All deep tendon reflexes were absent. Plantar responses were flexor bilaterally. Nerve conduction studies of both common peroneal and posterior tibial nerves showed prolonged distal latencies, grossly diminished amplitudes and velocities. Sensory nerve conduction in both upper and lower limbs was absent. F-wave latencies were diminished in both upper and lower limbs. These findings were suggestive of mixed demyelinating and axonal neuropathy involving both motor and sensory nerves and radiculopathy-consistent with a diagnosis of Guillain-Barre syndrome (GBS). A study of the cerebrospinal fluid revealed no cells, but a protein content of 500 mg%, confirming the diagnosis of GBS. As the patient could not afford intravenous immunoglobulin and plasmapheresis, he was not given any specific treatment. He did not have further progression of weakness and respiratory muscles or facial nerve was not involved. He improved gradually and was discharged 22 days later (day 27) when his muscle strength was 4/5 in all four limbs.

Case 2

A 25-year-old male presented with the complaints of fever with chills and rigor accompanied with severe headache, vomiting, convulsions, and altered sensorium for 6 days. He had no history of recreational drug use, diabetes, and hypertension. He also did not reveal any history suggestive of renal parenchymal disease or vasculitis.

On examination, he was comatose, febrile (102°F), pulse – 130/min, and BP – 140/70 mm Hg. Neurological examination revealed a comatose patient with bilateral constricted sluggish-reacting pupils without other cranial nerve deficits. Plantar response was bilaterally extensor. There was decerebrate posturing and neck rigidity was mild. Cardiovascular examination revealed no abnormality of peripheral pulses, bruits or cardiomegaly. Respiratory and abdominal examination revealed no abnormality.

Blood counts revealed a normocytic, normochromic anemia (hemoglobin – 9.7 g/dl, mean corpuscular volume – 90 fl), ESR – 28 mm/h, and platelet count of 75,000/cu.mm. Thick and thin blood smears were prepared and it revealed ring forms and gametocytes of P. falciparum and immunochromatographic test for PfHRP-2 based assay (ICT, Access Bio. Inc., NJ, USA) was strongly positive. Biochemical investigations – LFTs, renal function tests, and serum electrolytes were within the normal limits. No abnormality was found on urine examination with respect to proteinuria, red blood cells, white blood cells or casts. Enzyme-linked immunosorbent assay for human immunodeficiency virus was negative.

A clinical diagnosis of cerebral malaria caused by P. falciparum was established, and the patient was started on intravenous artesunate therapy. Following a lack of improvement in sensorium despite 3 days of antimalarial treatment, a non-contrast computed tomography (CT) scan brain was advised, which surprisingly revealed subarachnoid hemorrhage (SAH) [Figure 1]. A coagulation screen was found to be within normal range. Prothrombin time-international normalized ratio was 1.3 and activated partial thromboplastin time was 32 s. Fibrin degradation products by D-dimer were negative. A magnetic resonance angiography was carried out, which revealed no arterio-venous malformation or aneurysm. Anti-nuclear antibody titers were found to be negative by standard method. There was no family history of sickle cell anemia, and a sickling test on peripheral blood smear using sodium metabisulfite was negative.

Figure 1

Non-contrast computed tomography scan brain showing subarachnoid hemorrhage (SAH). Black solid arrows indicating SAH

The patient had a stormy clinical course and ultimately died 3 days later in spite of aggressive treatment with intravenous artesunate and supporting ventilator measures.

CONCLUSIONS

About 27% population in India lives in malaria high transmission areas (≥1 case per 1000 population).[2] Malaria is a major health problem in developing countries and P. falciparum malaria accounts for the most severe clinical manifestations. Severe falciparum malaria is characterized by hypoglycemia, lactic acidosis, non-cardiogenic pulmonary edema, renal impairment, and cerebral complications.[3] Cerebral malaria is the most dreaded complication and despite treatment, is associated with death rates of ~20% among adults.[4] Unusual complications, such as subdural empyema and intra-cerebral hemorrhage are exceedingly rare. GBS and SAH following malarial illness are the rare entity in literature.[4567] Eight of the cases of GBS were following P. falciparum infection and three were following Plasmodium vivax infection. Four patients with falciparum malaria developed severe paralysis with respiratory failure, and three patients died as per the previous medical literature.[8]

The pathogenesis of GBS following malaria infection is still not known. This is likely to be immunogenic. Other mechanisms of development of GBS following a parasitic infection include parasitic emboli obstructing vasa nervorum, release of neurotoxins, immune-mediated capillary damage, release of free radicals and tumor necrosis factor.[9] SAH in malarial illness was previously reported from other parts of India except East zone.[4567] Hence, this is the first case from the eastern part of India. Pathogenesis of SAH is still unknown. The neuropathological hallmark of cerebral malaria is the sequestration of erythrocytes containing parasites in cerebral capillaries and venules. Infection with P. falciparum leads to an increase in serum TNF-α, whose concentrations correlate well with the severity of disease.[10] By up regulating endothelial adhesion molecules, TNF-α may promote cerebral sequestration of platelets and red cells, thus leading to hemorrhage.[11] The SAH in our patient may have been caused by the rupture of a small vessel plugged by red cells combined with thrombocytopenia and perhaps due to masked hypertension.

Our reported case of SAH in falciparum malaria, which is the rare entity in the medical literature, is the first reported case from the eastern part of India. Though the exact pathophysiological mechanism is not known, this case shows that research is needed in this area. GBS due to malaria, another rare entity, which may happen due to immunological reaction, was successfully treated without intravenous immunoglobulin and respiratory support. These two uncommon cases should alert the clinicians, neurologists, and tropical disease epidemiologists about the diversity of presentation of malaria in tropics.