Cerebellar ataxia a unique initial presentation of Legionnaires’ disease

Abstract

We present a case of Legionnaires’ disease complicated by cerebellar ataxia. A 60-year-old man was diagnosed with Legionnaires’ disease by urine antigen after presenting to the hospital with a main problem of headache and gait instability. He also had a productive cough, as well as nausea, vomiting and diarrhoea. Initial physical examination revealed a positive Romberg test, positive pronator drift, severely unsteady gait and bilateral upper extremity resting tremors with the remainder of cranial nerves and neurological examination being unremarkable. The patient had a prolonged hospital course requiring endotracheal intubation and mechanical ventilation. He received 14 days of levofloxacin with resolution of the pneumonia. On repeat assessment prior to discharge, the patient’s neurological symptoms improved; however, he still had mild residual gait instability, dysdiadokinesia and difficulty with fine motor tasks such as writing. Romberg test remained positive.

Background

The clinical manifestations of Legionnaires’ disease is predominated by respiratory symptoms; however, systemic features affecting the kidney and central nervous system (CNS) have been described as well.¹ Neurological manifestations such as headache and confusion are not uncommon, whereas cerebellar ataxia and dysarthria are rare extrapulmonary manifestation of Legionnaires’ disease.² These manifestations can be devastating to patients as they can last up to 3 years after resolution of the pulmonary disease.¹ This case is unique given the unusual history of presentation, as well as the rare occurrence of cerebellar symptoms such as cerebellar ataxia and dysarthria in Legionnaire’s disease, which can cause significant morbidity.

Case presentation

A 60-year-old man with a medical history significant for hypertension and chronic kidney disease was presented to the emergency department for severe gait instability. Per patient, he never experienced any gait abnormalities prior to this episode and was physically very active. His symptoms started approximately 6 days prior to presentation and were accompanied by dysarthria, headache, productive cough, nausea, vomiting and diarrhoea. The patient’s initial physical examination was significant for tachycardia of 104 beats/min, fever of 40°C and decrease lung sounds in left posterior lung field as well as left sided expiratory crackles. Patient was alert and oriented to person, place and time; however, he was in mild distress and slightly agitated. His neurological examination revealed bilateral upper extremity tremors, pronator drift, a positive Romberg sign and wide-based gait with marked instability. The patient did not demonstrate horizontal or vertical nystagmus, and his examination revealed normal extraocular eye movements, fine touch and pinprick of the face; the trunk and extremities were normal. His sensory examination was grossly intact, deep tendon reflexes of upper and lower extremities were normal and plantars were flexor. The remainder of the neurological examination was unremarkable.

The patient’s social history was relevant for his occupation as a contractor. He stated that prior to falling ill, he was renovating an older house where he was replacing the ventilation system. Patient recalls removing a large pipe with stagnant water the day prior to symptoms starting. Several of the patient’s younger coworkers developed flu-like illnesses around the time he became ill. The patient’s social history was also significant for alcohol use disorder, with patient endorsing 2–3 24 oz cans of beer per day, for the past 20 years.

Investigations

Haemoglobin: 14.5 mg/dL, MCV 89, WBC 18 K/cumm, platelets 324 K/cumm.

Na 130 mMol/L, K 3.9 mMol/L, Cl 94 mMol/L, HCO3 20 mMol/L, BUN 28 mg/dL, creatinine 2.4 mg/dL.

AST 316 unites/L, ALT 99 unites/L, Alk phos 170 unites/L, total bilirubin 0.5 mg/dL, direct bilirubin 0.3 mg/dL.

Urine Legionella antigen: Positive.

Streptococcus pneumoniae antigen: Negative.

Blood culture: No growth (Finalized)

B₁₂ and Folate: Within Normal Limits

Imaging: (figures 1–3).

Figure 1.

(A) Chest X-Ray—PA view. (B) Chest X-Ray—PA lung window. (C) Chest X-Ray—Lateral view. Impression: left upper lobe and lingular consolidation consistent with pneumonia. PA, Posterior-Anterior

Figure 2.

(A) CT head—horizontal view. (B) CT head—sagittal view. (C) CT head—coronal view. Impression: negative for acute haemorrhage or midline shift. No evidence of cerebellar atrophy or haemorrhage of mammillary bodies.

Figure 3.

(A) MRI—T1: mammillary bodies (arrow), no intracranial haemorrhage, extra-axial fluid collection, mass or abnormal enhancement. (B) MRI—T2/FLAIR: no foci of bright signal demonstrated on the T2/FLAIR sequences. (C) MRI—DWI: diffusion-weighted image demonstrates no recent infarct or other diffusion abnormality. FLAIR, fluid attenuation inversion recovery.

Lumbar Puncture: colourless fluid, WBC 1, RBC 1, normal protein.

Differential diagnosis

Wernicke-Korsakoff syndrome is a possibility given his history of alcohol use; however, he did not have the classic triad (oculomotor dysfunction, encephalopathy and ataxia) of clinical symptoms. Caine’s criteria for diagnosis of Wernicke encephalopathy, which requires patients to have two of four criteria including dietary deficiencies, oculomotor abnormalities, cerebellar dysfunction and altered mental status or impaired memory, have been shown to be more sensitive than imaging, or the classic triad of altered mental status, ataxic gait and ophthalmoplegia.³ Our patient displayed only cerebellar dysfunction, making Wernicke encephalopathy unlikely. Furthermore, our patient received thiamine on admission, and symptoms did not improve.

Another possible diagnosis is alcohol withdrawal could be consistent with the patient's neurological findings; however, less likely as our patient’s cerebellar dysfunction persisted at the time of his discharge approximately 17 days after his last alcoholic consumption.

Treatment

Patient was initially started on cefepime, vancomycin and azithromycin along with aggressive intravenous fluid resuscitation. The patient developed severe respiratory distress requiring intubation and was transferred to the intensive care unit (ICU). At that time, he experienced diffuse tremors. The calculated Clinical Institute Withdrawal Assessment of Alcohol Score was elevated. Treatment for alcohol withdrawal was initiated with thiamine, folate, lorazepam and chlordiazepoxide.

On the second day of admission, the Legionella urine antigen tested positive and his antibiotic regimen changed to levofloxacin for targeted therapy. The patient had a prolonged ICU stay where he received a total of 14 days of levofloxacin.

Outcome and follow-up

Patient was hospitalised for 17 days, and at the time of discharge his pulmonary symptoms resolved; however, his neurological manifestation remained. Follow-up with patient >90 days after his presentation revealed complete resolution of his neurological symptoms with return to normal baseline in terms of performance of daily activity.

Discussion

A review article published in 2004 detailed 29 cases of Legionella manifesting as cerebellar dysfunction. Of these 29 cases, dysarthria (79%) and ataxia (72%) were the two most common symptoms.¹ In this study; all but four patients the pulmonary symptoms preceded the neurologic deficits by an average of 4.5 days. Our case is unique, as our patient’s neurologic symptoms began the same day as his pulmonary symptoms were the predominant symptoms. Cerebrospinal fluid (CSF) was tested in 16 of the cases, with 13 patients having no abnormalities, as was the case with our patient. The remaining 3 patients had elevated white cell counts, red cell counts and protein; however, culture and gram stain were negative in all 16 patients.

Ohta et al described two patients with Legionella pneumonia that manifested as prolonged neurologic deficits.⁴ The first patient exhibited difficulty in walking and was unable to stand on his own. The second patient who lived in the same apartment complex and shared a bathroom presented with severe headaches and tremors, as our patient did. These patients continued to have mild neurological deficits at time of discharge, which persisted for 68 and 24 days, respectively. In both patients, as with ours, CT and MRI were normal. Single-photon emission computed tomography (SPECT) imaging was obtained which showed hypoperfusion to cerebellar, and frontal lobes, but unfortunately we did not obtain SPECT imaging for our patient.⁴ Kunimasa et al reported a case of Legionella pneumonia where diffusion-weighted MRI showed marked hyperintensities in the corpus callosum on day 2 of presentation, which resolved after 2 weeks.⁵ Given our patient’s clinical instability, we were unable to obtain MRI until day 15 of hospitalisation, which was likely too late to capture any potential abnormalities on MRI.

The pathophysiology of cerebellar involvement of Legionella is unknown. In the absence of a direct invasion of the CNS, as in our patient, several theories exist; a toxin-mediated and an immune-mediated mechanism have been hypothesised.⁶Legionella is known to produce multiple toxins: exotoxins, cytotoxins, endotoxin-like material, hemolysin and protease; however, their role in disease has been unknown.^7–9 The toxin-medicated process has the potential of contributing to both pulmonary and extrapulmonary symptoms of Legionnaires’ disease; nonetheless the type of toxin contributing to extrapulmonary symptoms is yet to be determined.^{8 9} Another theory attributes the neurological symptoms to an immune-mediated process; this theory has been supported by cases of disseminated Legionella encephalomyelitis in which symptoms responded to steroids.¹ Recent studies have been shown that Legionella Pneumophila has the ability to activate retinoic acid-inducible gene 1-like receptors, Toll-like receptors and nucleotide-binding oligomerisation domains-like receptors, which are responsible for regulating the innate immune response and activation of inflammasome pathway. The activation of the inflammasome pathway, which may be peripheral or within CNS, induces pyroptosis, a highly inflammatory cell death pattern that occurs to remove this intracellular pathogen, which may be the cause of CNS dysfunction.¹⁰ There are multiple intracellular and extracellular factors that affect the virulence of Legionnaires’ disease bacterium; this along with host immune status may explain why the neurological effects are rare. The last theory is that Legionella directly invades the CNS; this is unlikely as most brain imaging and CSF studies are negative.

Learning points.

• Legionnaire’s disease can present with cerebellar ataxia, which may last a long time and can often be devastating.

• Currently, the only known treatment is with fluoroquinolones or macrolides for the underlying pneumonia.

• Symptoms usually last up to 60 days in immunocompetent host; however, it has been reported to last up to 3 years.

• The mechanism of cerebellar manifestations is unknown; toxin-mediated and immune-mediated mechanisms have been hypothesised. Further research is needed to understand the pathophysiology of cerebellar ataxia in patients with Legionnaires to developed targeted treatment.