Behavioural change: a rare presentation of leptospirosis

Abstract

Neurological manifestations of leptospirosis without severe multiorgan involvement are a rare clinical entity. Despite the increasing prevalence of the disease in many tropical countries, its protean clinical presentations make its timely diagnosis challenging. We report the case of a 44-year-old Filipino man presenting with fever, myalgia, behavioural changes and altered sensorium. Neurological examination did not show any focal neurological deficits or clear signs of meningoencephalitis. Lumbar tap, cranial CT scan and cranial MRI were inconclusive. The diagnosis of leptospirosis with acute encephalitis relied heavily on the patient’s clinical clues, appropriate exposure history and patterns in ancillary laboratory tests. Empiric antibiotic therapy with ceftriaxone was initiated. Seroconversion and fourfold increase in serological antibody titres by leptospirosis microagglutination test later confirmed the diagnosis. The patient was successfully treated, and all neurological complications were reversed.

Background

Leptospirosis is a prevalent endemic zoonotic disease and a growing public health problem in tropical countries. The estimated incidence reported by the WHO is 0.1 to as high as 10 or more per 100 000 people living in temperate and tropical countries, respectively,¹ many of which may still be under-reported due to its highly variable and non-specific clinical presentation. The most common manifestations include fever, myalgia and headache usually occurring after an incubation period of 2–26 days. It rarely presents as a primary neurological disease.² We report a case of a man who consulted at the emergency room for altered sensorium, behavioural changes and seizures which were later found to be uncommon presenting symptoms of leptospirosis.

Case presentation and investigations

A 44-year-old apparently well truck driver from Manila, Philippines, was brought to the emergency room for decrease in sensorium. One week prior to illness, the patient was wading in floodwaters on his way home, when he sustained a wound on his left toe with subsequent swelling and discharge. Four days after, he was noted to develop fever, generalised weakness and mild behavioural change. The wife described him as having increased irritability, preferring to stay in bed for most of the day. The patient also had generalised weakness, poor appetite and myalgia. There was no cough, abdominal pain, nausea or vomiting, loose stools, dysuria, haematuria, or changes in urine output. Symptoms were tolerated until a few hours prior, he was noted by his wife to have bilateral stiffening of upper extremities, upward rolling of eyeballs lasting a few seconds, then was noted to be unresponsive, prompting consult at the emergency room.

On initial examination, he was febrile with a temperature of 38.9°C, blood pressure 100/60 mm Hg, heart rate of 136 beats per minute and respiratory rate of 22 breaths per minute. He had a severely depressed sensorium (Glasgow Coma Scale of 7), and was immediately intubated for airway protection with note of oral lacerations involving the both side of the tongue, with minimal bleeding and blood clots and minimal clear, and non-bloody endotracheal secretions. Capillary blood glucose was 107 mg/dL. Initial neurological examination showed intact cranial nerves; however, all extremities were non-reactive to pain. All reflexes were normal. There were no signs of meningeal irritation such as nuchal rigidity, Kernig or Brudzinski signs. A few hours after, patient was less drowsy, although there was note of persistent behavioural changes. He remained agitated and disoriented to person, time and place.

The rest of his physical examination revealed conjunctival suffusion, anicteric sclerae, clear breath sounds and an abrasion on the left big toe with note of minimal purulent discharge. There was no note of rash, signs of bleeding, jaundice, abdominal distention or tenderness.

He had no history of smoking, alcohol abuse or illicit drug use. There was no history of recent travel. He has been married for more than 10 years with no history of sexual promiscuity.

The patient was thus diagnosed to have probable leptospirosis. An initial plain cranial CT scan was done revealing suspicious hypodensities in the midbrain, for which acute infarcts could not be ruled out (figure 1A). Behavioural change was initially considered to be either encephalopathy of possible metabolic or septic aetiology. Ceftriaxone was started empirically. Intravenous hydrocortisone was given at the emergency room empirically while awaiting chest X-ray.

Figure 1.

(A) Plain cranial CT image showing a suspicious hypodense focus in the midbrain (circle). (B) Repeat plain cranial CT no longer shows the suspicious hypodense focus with no other significant findings.

Complete blood count revealed a haemoglobin of 162 g/L, a haematocrit of 0.49, a platelet count of 250×10⁴/L and white blood cell (WBC) count of 16×10⁹/L with 67% neutrophils, 20% lymphocytes, 5% monocytes and 7% eosinophils.

Initial serum creatinine was 237 µmol/L (N:58–110) with a computed clearance of 35 mL/min via Cockroft-Gault formula. Blood urea nitrogen–creatinine ratio was 11.4. With antibiotics and hydration, serum creatinine decreased by half to 112 µmol/L and improved creatinine clearance to 73 mL/min by the second hospital day. Urine output remained adequate at 0.5–1 cc/kg/hour. Serum sodium, potassium, corrected calcium and magnesium remained normal at 144, 4.3, 2.13 and 0.7 mmol/L, respectively. Urinalysis showed proteinuria (albumin +2), haematuria (red blood cell (RBC) 68/high-power field (HPF)) with RBC morphology showing 21% dysmorphic RBCs, pyuria (WBC 14/HPF) and coarse granular casts. Urine culture did not isolate any organisms.

Liver enzymes were elevated 2–3 times normal with aspartate aminotransferase 191 IU/L (N: 17–59 IU/L) and alanine aminotransferase 126 IU/L (N:<50 IU/L). Total creatine kinase and creatine kinase isozyme MB were also elevated at 706 IU/L (N: 55–170) and 60.8 IU/L (N: 0–16). Bilirubins, alkaline phosphatase, protime and partial thromboplastin time remained normal. Abdominal ultrasound was unremarkable.

Chest X-ray showed no signs of pulmonary haemorrhage, and the patient never developed clinical signs and symptoms of dyspnoea or haemoptysis; hence, hydrocortisone was discontinued and patient was extubated.

Ancillary tests such as urine methamphetamine, cannabinol/marijuana (MET/THC) test, serology for syphilis (rapid plasma reagin test), peripheral smear for malarial parasite, dengue NS1, dengue IgM and Salmonella IgM were negative. Hepatitis profile showed past hepatitis B infection.

Delirious and disoriented behaviour worsened on his third hospital day (day 7 of illness) with episodes of waxing and waning sensorium, inappropriate speech, visual and auditory hallucinations frequently citing he could see and hear family members who were not there. He was unable to recognise his wife and son. Cranial MRI with gadolinium contrast was ordered but was unavailable at our institution at this time. A follow-up plain cranial CT scan was done revealing essentially unremarkable findings (figure 1B). There were no masses or signs of hydrocephalus. Lumbar tap showed that the cerebrospinal fluid (CSF) was clear, with normal opening pressure (18 cmH₂0). CSF analysis showed 0 RBC/µL, 5 WBC/ µL with lymphocytic predominance. CSF protein level was mildly elevated at 60 mg/dL, and CSF glucose was 74.55 mg/dL (56% of capillary blood glucose). CSF gram stain, India ink stain, acid-fast stain and cultures did not isolate any bacteria or encapsulated organism. CSF herpes simplex virus PCR was negative.

Paired sera for leptospirosis microscopic agglutination test (MAT) taken on admission (day 4 of illness), 4th (day 8 of illness) and 7th hospital day (day 11 of illness) showed seroconversion (initially negative, then positive at 1:400 dilution, and a fourfold rise at 1:1600 dilution). This confirmed the diagnosis of leptospirosis. CSF leptospirosis culture taken on his second hospital day was negative; however, this was taken after the administration of antibiotics.

Cranial MRI with gadolinium contrast was only available on his ninth hospital day (day of discharge). By this time, the patient responded to antibiotic given, with marked improvement in sensorium and gradual resolution of disorientation, agitation and behavioural change. Imaging revealed non-specific, patchy, ill-defined T2- weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) hyperintense signals located at the bilateral, frontal subcortical white matter and left external capsule (figure 2A-D).

Figure 2.

MRI with gadolinium contrast showing (A) T2WI bright signals in the subcortical deep white matter region of both frontal lobes (arrows). (B) T2 FLAIR sequence showing non-suppression of the bright signals (arrows) in the said regions. (C) T2WI bright signal in the left external capsule (circle), (D) which exhibits non-suppression in T2-FLAIR sequence (circle).

Differential diagnosis

The differential diagnoses for our patient was broad. This included drug intoxication, metabolic encephalopathy, urosepsis, typhoid encephalitis, acute viral encephalitis and dengue fever. Drug intoxication was initially considered; however, it was ruled out because of negative rapid urine MET/THC testing. Metabolic encephalopathy was ruled out since serum electrolytes were all within normal limits. Urosepsis was ruled out due to the absence of urinary tract symptoms and negative urine cultures. Majority of patients with enteric fever present with chills, fever and abdominal pain. Gastrointestinal symptoms were not prominent in our patient, and ELISA Salmonella IgG and IgM were negative; thus, typhoid encephalitis was also unlikely.

Acute viral encephalitis from Japanese encephalitis virus (JEV) and dengue virus may present similarly with non-specific symptoms such as fever, generalised weakness, myalgia and behavioural change. JEV is endemic in the Philippines; and may be a differential diagnosis; however, it presents more commonly with focal neurological deficits (paresis, plegias and cranial nerve palsies) and hyponatremia from syndrome of inappropriate antidiuretic hormone secretion. MRI abnormalities in JEV are more commonly seen in the thalamus, basal ganglia, midbrain, pons and medulla. Cases reported in the Philippines are more commonly seen in patients who live near rice fields, pig farms and other rural areas, rather than urban cities, which makes the diagnosis less likely. Dengue fever may also have a similar clinical picture; however, laboratory investigations usually reveal leucopenia, haemoconcentration and thrombocytopenia which was not seen in this case. More importantly, dengue serology was negative. Malaria is a third differential and may present similarly to leptospirosis, but is only endemic in some cities of the Philippines such as Palawan, and is almost never seen in cities such as Metro Manila. Our patient lived in a metropolitan city, with no history of recent travel. Peripheral smear for malarial parasite was also negative.

Treatment

Although the initial serological leptospirosis MAT was negative, we opted to continue empiric antibiotic therapy with ceftriaxone for the diagnosis of leptospirosis based on his clinical presentation and laboratory parameters.

Organ dysfunctions, namely the patient’s kidneys, liver, central nervous system, were managed by supportive therapy. He was referred to psychiatry for symptomatic treatment of agitation and insomnia and was started on as needed haloperidol and clonazepam. Haemodialysis and diuretic use were not needed during the course of his admission. Urine output, serum creatinine, potassium, magnesium and liver function tests were monitored with notable decrease in trends, with hydration and antibiotics (table 1).

Table 1.

Blood chemistry results

Serum chemistry	Reference range	Admission	Hospital day 2	Hospital day 7	Follow-up
Sodium	135–145 mmol/L	144	143	139
Potassium	3.5–4.5 mmol/L	4.3	4.2	4.7
Calcium (corrected calcium)	2.12–2.52 mmol/L	2.13	2.11	2.2
Magnesium	0.7–1.05 mmol/L	0.7	0.72	0.77
Bun urea nitrogen	3.2–8.0 mmol/L	11	11.2	6.4
Creatinine	53–115 umol/L	237	112	76	72
albumin	38–51 g/L	39		36
Aspartate aminotransferase	17–59 U/L	191	156	72	42
Alanine aminotransferase	<50 IU/L	126	101	77	40

The patient completed 7 days of ceftriaxone. Behaviour gradually improved throughout his hospital stay and returned to normal on his ninth hospital day.

Outcome and follow-up

Patient was discharged awake, ambulatory, coherent, conversant and oriented to person, time and place. There was no recurrence of seizures or hallucinations. He followed up 1 month after at the out-patient clinic with no complaints. His complete blood count, liver function tests and serum creatinine were all within normal limits (table 1). The patient opted not to do a follow-up cranial MRI study due to financial constraints.

Discussion

Leptospirosis forms a broad spectrum of clinical manifestations ranging from mild, anicteric, flu-like illness, to the classic, severe case of leptospirosis called Weil’s syndrome, comprising of jaundice, renal dysfunction and bleeding diasthesis.^{3 4} Its varied clinical presentation may cause delays in diagnosis and management despite its high incidence in a tropical country such as the Philippines.

The modified Faine’s criteria is a tool commonly used by the WHO to aid in the recognition and diagnosis of this disease, particularly in resource-limited settings. It includes the scoring of several common clinical data, epidemiological risk factors, bacteriologic or laboratory findings to make a presumptive or confirmed diagnosis of leptospirosis. In the Philippines, we follow similar local guidelines released by the local Leptospirosis Task Force group, which state that ’any individual presenting with acute febrile illness of at least two days, and at least two of the following symptoms: myalgia, calf tenderness, conjunctival suffusion, chills, abdominal pain, headache, jaundice, or oliguria; with risk factors of exposure such as residing in a flooded area, wading in floods and contaminated water, contact with animal fluids, with or without cuts or wounds should be considered a suspected leptospirosis case’.⁴

This patient satisfied the criteria for suspected leptospirosis: 4-day history of fever, non-specific myalgia and conjunctival suffusion after wading in floodwaters. However, this case is unique since his symptoms of suspected seizures and behavioural change were the initial and more prominent presentation of his disease. It is also important to note that serological titres such as leptospirosis MAT may initially be negative, especially if tested early in the course of a patient’s illness.

The diagnosis of probable acute encephalitis was considered on the basis of the case definition released by the International Encephalitis Consortium.⁵ He had alteration in mental status and behavioural changes for more than 24 hours with no alternative cause identified. His serum electrolytes were within normal limits. He had elevated transaminases but not enough to cause jaundice, severe liver injury or hepatic encephalopathy. Serum creatinine quickly improved, urine output remained adequate; thus, the possibility of uraemic encephalopathy was less likely. His associated symptoms of fever, generalised seizure and borderline CSF pleocytosis gave further support to the diagnosis. There are several grey areas when considering encephalitis. It may have been possible that because of our empiric glucocorticoid therapy, the CSF failed to mount an inflammatory response; hence, CSF WBC was not markedly elevated. If the lumbar tap was taken too early in the course of the disease, pleocytosis might not also be as prominent. It is important to recognise that encephalitis can also occur without significant CSF pleocytosis, non-specific neuroimaging abnormalities, normal opening pressures or negative cerebrospinal cultures⁵ as in this case.

Diagnostic tests rely heavily on the time during the course of the illness the patient presents. This is because leptospirosis is a biphasic disease. In the early septic phase, symptoms of viral illness are prominent, and occasionally Leptospira species may be isolated in the CSF. It is during the later immunological phase where more classic signs of meningitis are seen. During this time, localisation of leptospires within the tissue is mediated by immune complexes, and as it is hypothesised, CNS manifestations are caused by the immunological reactions to the spirochetes rather than by direct invasion into the CNS, which could be the mechanism presented in our case.⁶

In a similar case reported by Puca and Majko,⁷ an 18-year-old female from Southern Albania presented with symptoms of fever, headache, photophobia, vomiting and generalised myalgia. Physical examination did not show any focal neurological deficits or signs of meningeal irritation. Lumbar tap revealed only slightly elevated opening pressures, CSF pleocytosis and negative CSF cultures. Serum samples for more common causes of encephalitis in their country, such as West Nile virus, rikketsia, tick-borne encephalitis, influenza and brucellosis were all negative. Serological ELISA IgM test confirmed the diagnosis of leptospirosis. Empiric ampicillin therapy was completed. In another case report by Wang and Han,⁸ a 37-year-old Taiwanese cook working in a restaurant near a waste recycling station and fishing pond presented primarily with signs and symptoms of meningitis with no pulmonary, hepatic or renal involvement. Lumbar tap was consistent with aseptic meningitis. The patient was also treated empirically with penicillin while awaiting serological confirmation. The diagnosis of leptospirosis was clinched after treatment was completed, via leptospirosis MAT conversion in the acute and convalescent phase of his disease.

Primary neurological involvement is a rare occurrence in leptospirosis.⁸ The diagnosis of meningitis or encephalitis may be challenging since patients may lack other diagnostic hallmarks of severe leptospirosis.² A retrospective cross-sectional study in India found that among those presenting with acute neurological disease subsequently found to have leptospirosis, neurological manifestations usually manifest with signs and symptoms of aseptic meningitis, and are more commonly seen in the anicteric forms of leptospirosis.⁸ Encephalitis, transverse myelitis or Guillain-Barre syndrome, cerebellitis, or intracranial bleed may also occur in leptospirosis but are seldom seen.⁹ Radiological findings are variable. A retrospective study in a tertiary neurological centre in South India found normal CT findings in 67% of patients diagnosed with neuroleptospirosis. A minority showed non-specific cerebral oedema.¹⁰ A case report by Singh et al showed reversible T2W-hyperintense and FLAIR hyperintense signals in the subcortical white matter, pons, cerebellum, basal ganglia and brainstem of a patient diagnosed with leptospirosis.¹¹ Similarly in this present study, cranial MRI with gadolinium contrast revealed non-specific, patchy, ill-defined T2W-hyperintense and Fluid-Attenuated Inversion Recovery (FLAIR) hyperintense signals located at the bilateral, frontal subcortical white matter and left external capsule (figure 2A-D). However, due to the financial constraint of the patient, a follow-up MRI was not done.

Leptospires are highly susceptible to a broad range of antibiotics. The drug of choice in most countries is still intravenous penicillin. Ceftriaxone, ampicillin and doxycycline are reasonable alternatives. Ceftriaxone was used in this patient for the convenience of once-a-day dosing. Aggressive supportive care with intravenous hydration and antipyretics is essential. Case fatality rate may range from 1% to 50% without proper antibiotic treatment^{12 13}; however, timely treatment decreases this rate significantly. As in our patient, early diagnosis usually relies heavily on a high index of suspicion: putting together clinical clues, risk factors, physical examination and patterns in laboratory tests.

Learning points.

• Leptospirosis may have atypical neurological presentations such as depressed sensorium, behavioural changes or seizures even in the absence of Weil’s syndrome.

• In the low-resource setting, the diagnosis of encephalitis in leptospirosis requires a high clinical index of suspicion.

• Our case illustrates that acute encephalitis from leptospirosis may not always present with significant cerebrospinal fluid pleocytosis or demonstrable neuroimaging abnormalities.

• With early identification, diagnosis and treatment of leptospirosis, most patients usually recover.