Cerebellar involvement in legionellosis.

Abstract: The involvement of the cerebellum in Legionnaires' disease has been noted in occasional case reports, but there have been no reviews on this subject to date. We report a previously healthy patient who contracted Legionella pneumonia and developed profound cerebellar dysfunction during his illness. He was treated with antibiotics with improvement of his pneumonia, but his cerebellar symptoms persisted. We review 29 case reports of cerebellar dysfunction in Legionnaires' disease and summarize the clinical course, cultures, cerebrospinal fluid analyses, and neuroimaging. Finally, possible methods of pathogenicity are discussed including data regarding direct bacterial invasion, toxin production, and immune-mediated mechanisms.

Key Words: cerebellum, legionella, neurologic, pathophysiology

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Legionnaires' disease was initially described as a pneumonic illness among delegates to the 1976 American Legion convention in Philadelphia. (1), (2) Although respiratory symptoms dominate the clinical picture, early investigators also recognized systemic involvement, including the kidneys and the central nervous system. (3-5) Encephalopathy, manifested by confusion or even coma, is the most common neurologic symptom; the severity is often out of proportion to metabolic derangements, suggesting a specific effect of the legionnaires' bacterium on the central nervous system. (4), (6) Although the neurologic symptoms usually resolve with time, some patients have persistent deficits, especially in cerebellar function. (6) A case of persistent cerebellar dysfunction that occurred during treatment of Legionella pneumonia is presented, followed by a review of the literature for reports of cerebellar involvement in legionellosis. Finally, the neuropathology of Legionnaires' disease is examined for possible causes of neurologic dysfunction in this infection.

Methods

A computer-based search of the English literature (MED-LINE, National Library of Medicine, Bethesda, MD; years 1976-2003) was performed. Key words used in the search were Legionella, legionellosis, legionnaires' disease, neurology, neurologic dysfunction, cerebellum, cerebellar dysfunction, and pathology. The citations in all identified articles were evaluated, and all titles not previously found via the computerized search that contained the key words were reviewed.

Results

We found 29 cases of Legionnaires' disease, including the one described above, in which cerebellar dysfunction was described as the primary neurologic manifestation (Table 1). (4) (6-19) Dysarthria and ataxia were the cerebellar symptoms most frequently reported, occurring in 23 (79%) and 21 (72%) cases, respectively. Dysmetria, nystagmus, and dysdiadokinesia were each reported in three cases (10%), although all of these findings may not have been searched for or reported in all cases. In addition to cerebellar signs, 23 patients (79%) were confused and 5 (17%) had evidence of peripheral neuropathy during their illness.

Nineteen of the patients had previous medical histories reported; of these, 12 (63%) had no underlying illnesses. Two patients had bipolar disorder, and one each had a history of alcoholism, hypothyroidism, major depression, hereditary spherocytosis, and urticaria. The two patients with bipolar disorder received lithium, whereas the patient with urticaria received prednisolone before presentation. The average age at presentation was 47 years old.

Twenty-five (86%) of the 29 patients had evidence of pneumonia at the time of admission. The four patients without pneumonia were three young children who presented with ataxia alone and one adult whose chief complaint was diarrhea. The average time from the onset of pulmonary symptoms to the onset of cerebellar symptoms was 4.5 days.

Reported investigations into the cause of the cerebellar dysfunction included lumbar punctures, EEGs, and CT scans of the brain. Analysis of cerebrospinal fluid was reported 16 times; 13 (81%) analyses were normal, whereas one each had elevated red blood cells, white blood cells, and total protein. No cerebrospinal fluid examinations had positive stains or cultures. Six (60%) of the 10 EEGs revealed diffuse slow-wave activity consistent with toxic encephalopathy, three were reported as normal, and one showed changes consistent with "brainstem encephalitis." Eight (80%) of the 10 CT scans were normal. One CT scan showed cerebellar atrophy noted after a prolonged period in a patient with persistent ataxia, and another revealed mild ventricular enlargement.

Long-term neurologic follow-up was available for 17 patients. Five (29%) recovered completely or nearly completely, although three of these were the young children who presented with ataxia alone. Twelve (71%) had significant persistent deficits of speech or gait, with the longest period of observation reported as 3 years.

Discussion

Infections that primarily result in cerebellar dysfunction are rare, with the most common being acute cerebellar ataxia of childhood that has been attributed to various viruses including echo, Coxsackie groups A and B, Epstein-Barr, and herpes simplex. (20) Involvement of the cerebellum in legionellosis and the persistence of ataxia were noted among the first patients diagnosed with the disease. (6) Johnson et al (17) reviewed 912 cases of Legionnaires' disease and estimated the incidence of cerebellar dysfunction at 3.7%, with limb ataxia and speech disturbances being the most common manifestations.

All but four of the cases of legionellosis with cerebellar involvement have been preceded by pulmonary findings. (15), (16) Ataxia and dysarthria are the most common symptoms and arise a few days to 1 week after the onset of illness. A majority of cases have accompanying confusion, and peripheral neuropathy may also be seen. Abnormalities on analysis of cerebrospinal fluid or cranial CT scanning are rare, whereas the EEG often shows diffuse slowing consistent with toxic encephalopathy or may be normal. The cerebellar dysfunction, especially the ataxia and dysarthria, tends to persist, in contrast to other neurologic symptoms, which seem to resolve within weeks to months.

In addition to cerebellar involvement, a variety of neurologic manifestations of Legionnaires' disease have been described ranging from encephalomyelitis to peripheral neuropathy to myositis. (12), (21), (22) The pathogenesis of the neurologic dysfunction in Legionnaires' disease remains speculative at present. Dissemination of the bacterium from a pneumonic focus has been demonstrated, with the most common sites being the hilar lymph nodes, spleen, kidney, heart, and bone marrow. (23-25) However, the presence of legionella in the nervous system has been established in only rare instances. A review of 183 autopsy reports found only two cases of demonstrable organisms in the central nervous system. (17), (22), (26-29) The vast majority of neurologic radiographic studies and analyses of cerebrospinal fluid have been normal, which adds further support to the notion that Legionella does not usually affect the nervous system directly.

In the absence of direct invasion of the central nervous system, Legionella could produce neurologic symptoms by either production of a neurotoxin or by immune-mediated mechanisms. Although no legionella-produced neurotoxin has been found, a protease formed by Legionella pneumophila produces hemorrhagic pneumonia in the absence of proliferating organisms. (30) Studies of peripheral nerves involved in Legionella infection have produced findings similar to that induced by a toxic insult. (14) Researchers have noted that the multiple sites of neurologic involvement make cross-reactivity between neurologic tissue and Legionella antigens improbable and propose the production of an endotoxin-like agent as the likely cause. (14) Legionella species do produce an endotoxin-like substance, although it seems to be weaker than that produced by other Gram-negative bacteria. (31)

Support for immune-mediated mechanisms in the neurologic manifestations of Legionnaires' disease comes from observations of cases of acute disseminated encephalomyelitis and Guillain-Barre type peripheral neuropathy complicating legionellosis. (5), (12), (18), (22), (32), (33) The two patients with acute disseminated encephalomyelitis responded well to high-dose corticosteriods. However, direct findings in support of immuno-pathology such as decreased serum complement levels or biopsy specimens with evidence of vasculitis or immune complex deposition have thus far been lacking.

Conclusion

Although rare, the syndrome of cerebellar involvement during Legionella infection often profoundly affects previously healthy individuals. The cerebellar manifestations usually become apparent several days into the disease course. Clear risk factors and mechanisms for cerebellar dysfunction in legionellosis have yet to be identified. The only known treatment at present is therapy for the underlying Legionella infection. Deficits in speech and gait may persist for years.

Healing is a matter of time, but it is sometimes also a matter of opportunity.

--Hippocrates

Table 1. Case reports of cerebellar dysfunction in Legionnaires' disease
(a)

                             No. of       Cerebellar symptoms
Series (ref. no.)           patients       (no. of patients)

Friedman, 1978 (4)             3      Ataxia (2), dysarthria (2),
                                        dysdiadokinesia (1)

Terranova et al, 1978 (6)      1      Ataxia

Lees & Tyrrell, 1978 (7)       2      Dysarthria, dysmetria (1)

Saleh et al, 1980 (8)          1      Dysarthria

Shetty et al, 1980 (9)         1      Ataxia, dysarthria

Baker et al, 1981 (10)         1      Ataxia, dysarthria, nystagmus

Maskill & Jordan, 1981 (11)    1      Ataxia, dysarthria,
                                        dysdiadokinesia, dysmetria,
                                        nystagmus

Morgan & Gawler, 1981 (12)     1      Ataxia, dysarthria

Pearson & Dadds, 1981 (13)     1      Ataxia, dysarthria

Weir et al, 1982 (14)          8      Ataxia (8), dysarthria (8),
                                        dysmetria (1)

Nigro et al, 1983 (15)         3      Ataxia

Bamford & Hakin, 1982 (16)     1      Ataxia, dysarthria

Johnson et al, 1984 (17)       2      Dysarthria (2),
                                        dysdiadokinesia (1)

Bernardini et al, 1985 (18)    1      Ataxia, dysarthria,
                                        dysdiadokinesia, nystagmus

Heath et al, 1986 (19)         1      Ataxia, dysarthria

Present case, 2004             1      Ataxia, dysarthria

                            Time from disease
                               onset until
                               cerebellar       Investigations (no. of
Series (ref. no.)            symptoms (days)          patients)

Friedman, 1978 (4)                  4          CSF normal (2)

Terranova et al, 1978 (6)          NA          CSF normal (1)

Lees & Tyrrell, 1978 (7)            3          CSF normal (2), CT
                                                 normal(1)

Saleh et al, 1980 (8)               3          CSF normal, EEG normal,
                                                 CT
                                                 with hydrocephaly

Shetty et al, 1980 (9)              4          CSF normal, CT normal

Baker et al, 1981 (10)              2          CSF normal, CT normal

Maskill & Jordan, 1981 (11)         3          CSF normal


Morgan & Gawler, 1981 (12)          5          CSF with elevated protein

Pearson & Dadds, 1981 (13)          5          CSF normal, EEG with
                                                 brainsterm dysfunction

Weir et al, 1982 (14)               5          CSF with lymphocytosis
                                                 (1),
                                                 EEG with diffuse
                                                 slowing
                                                 (5), CT with cerebellar
                                                 atrophy (1)

Nigro et al, 1983 (15)        Simultaneous     CSF normal (1)

Bamford & Hakin, 1982 (16)    Simultaneous     NA

Johnson et al, 1984 (17)           NA          CSF and CT normal (2),
                                                 EEG
                                                 with diffuse slowing
                                                 (1)

Bernardini et al, 1985 (18)         3          CSF with 50 RBC/mm (3)

Heath et al, 1986 (19)              7          CSF, CT, EEG normal

Present case, 2004                  6          CT, MRI, EEG normal

                             Symptoms
Series (ref. no.)            at 90 days

Friedman, 1978 (4)           Persisted

Terranova et al, 1978 (6)    Persisted

Lees & Tyrrell, 1978 (7)     Persisted

Saleh et al, 1980 (8)        NA

Shetty et al, 1980 (9)       Persisted

Baker et al, 1981 (10)       Persisted

Maskill & Jordan, 1981 (11)  Persisted


Morgan & Gawler, 1981 (12)   Resolved

Pearson & Dadds, 1981 (13)   Persisted

Weir et al, 1982 (14)        Persisted (2),
                               resolved (1)

Nigro et al, 1983 (15)       Resolved

Bamford & Hakin, 1982 (16)   Persisted

Johnson et al, 1984 (17)     NA

Bernardini et al, 1985 (18)  Persisted


Heath et al, 1986 (19)       Persisted

Present case, 2004           Persisted

(a) CSF, cerebrospinal fluid; CT, computed tomographic scan of brain;
EEG, electroencephalogram; MRI, magnetic resonance imaging of brain; NA,
not available; RBC, red blood cells.

From the Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, and St. Luke's Episcopal Hospital, Houston, TX.

We received no financial support for the preparation of this article. We have no commercial or proprietary interest in any drug, device, or equipment mentioned in this article.

Reprint requests to Samuel A. Shelburne, MD, Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, BCM 286, Room N1319, Houston, TX 77030. Email: [e-mail]

Accepted September 30, 2003.

Copyright [C] 2004 by The Southern Medical Association 0038-4348/04/9701-0061

References

(1.) Fraser DW, Tsai TR, Orenstein W, et al. Legionnaires' disease: Description of an epidemic of pneumonia. N Engl J Med 1977;297:1189-1197.

(2.) McDade JE, Shepard CC, Fraser DW, et al. Legionnaires' disease: Isolation of a bacterium and demonstration of its role in other respiratory disease. N Engl J Med 1977;297:1197-1203.

(3.) Swartz MN. Clinical aspects of Legionnaires' disease. Ann Intern Med 1979;90:492-495.

(4.) Friedman HM. Legionnaires' disease in non-Legionnaires: A report of five cases. Ann Intern Med 1978;88:294-302.

(5.) Gregory DW, Schaffner W, Alford RH, et al. Sporadic cases of Legionnaires' disease: The expanding clinical spectrum. Ann Intern Med 1979;90:518-521.

(6.) Terranova W, Cohen ML, Fraser DW. 1974 outbreak of Legionnaires' disease diagnosed in 1977: Clinical and epidemiological features. Lancet 1978;2:122-124.

(7.) Lees AW, Tyrrell WF. Severe cerebral disturbance in Legionnaires' disease. Lancet 1978;2:1336-1337.

(8.) Saleh F, Rodichok LD, Satya-Murti S, et al. Legionnaires' disease: Report of a case with unusual manifestations. Arch Intern Med 1980;140:1514-1516.

(9.) Shetty KR, Cilyo CL, Starr BD, et al. Legionnaires' disease with profound cerebellar involvement. Arch Neurol 1980;37:379-380.

(10.) Baker PC, Price TR, Allen CD. Brain stem and cerebellar dysfunction with Legionnaires' disease. J Neurol Neurosurg Psychiatry 1981;44:1054-1056.

(11.) Maskill MR, Jordan EC. Pronounced cerebellar features in Legionnaires' disease. Br Med J (Clin Res Ed) 1981;283:276.

(12.) Morgan DJ, Gawler J. Severe peripheral neuropathy complicating Legionnaires' disease. Br Med J (Clin Res Ed) 1981;283:1577-1578.

(13.) Pearson SB, Dadds JH. Neurological complications of Legionnaires' disease. Postgrad Med J 1981;57:109-110.

(14.) Weir AI, Bone I, Kennedy DH. Neurological involvement in legionellosis. J Neurol Neurosurg Psychiatry 1982;45:603-608.

(15.) Nigro G, Pastoris MC, Fantasia MM, et al. Acute cerebellar ataxia in pediatric legionellosis. Pediatrics 1983;72:847-849.

(16.) Bamford JM, Hakin RN. Chorea after legionnaire's disease. Br Med J (Clin Res Ed) 1982;284:1232-1233.

(17.) Johnson JD, Raff MJ, Van Arsdall JA. Neurologic manifestations of Legionnaires' disease. Medicine (Baltimore) 1984;63:303-310.

(18.) Bernardini DL, Lerrick KS, Hoffman K, et al. Neurogenic bladder: New clinical finding in Legionnaires' disease. Am J Med 1985;78:1045-1046.

(19.) Heath PD, Booth L, Leigh PN, et al. Legionella brain stem encephalopathy and peripheral neuropathy without preceding pneumonia. J Neurol Neurosurg Psychiatry 1986;49:216-218 (letter).

(20.) Harding AE. Cerebellar and spinocerebellar disorders, in Bradley WG, Daroff RB, Fenichel GM, et al (eds): Neurology in Clinical Practice. Boston, Butterworth-Heinemann, 1996, vol 2, ed 2, pp 1773-1792.

(21.) Warner CL, Fayad PB, Heffner RR Jr. Legionella myositis. Neurology 1991;41:750-752.

(22.) Sommer JB, Erbguth FJ, Neundorfer B. Acute disseminated encephalomyelitis following Legionella pneumophila infection. Eur Neurol 2000;44:182-184.

(23.) Weisenburger DD, Helms CM, Renner ED. Sporadic Legionnaires' disease: A pathologic study of 23 fatal cases. Arch Pathol Lab Med 1981;105:130-137.

(24.) Evans CP, Winn WC Jr. Extrathoracic localization of Legionella pneumophila in Legionnaires' pneumonia. Am J Clin Pathol 1981;76:813-815.

(25.) White HJ, Felton WW, Sun CN. Extrapulmonary histopathologic manifestations of Legionnaires' disease: Evidence for myocarditis and bacteremia. Arch Pathol Lab Med 1980;104:287-289.

(26.) Andersen BB, Sogaard I. Legionnaires' disease and brain abscess. Neurology 1987;37:333-334.

(27.) Gatell JM, Miro JM, Sasal M, et al. Legionella pneumophila antigen in brain. Lancet 1981;2:202-203 (letter).

(28.) Cutz E, Thorner PS, Rao CP, et al. Disseminated Legionella pneumophila infection in an infant with severe combined immunodeficiency. J Pediatr 1982;100:760-762.

(29.) Van Arsdall JA II, Wunderlich HF, Melo JC, et al. The protean manifestations of Legionnaires' disease. J Infect 1983;7:51-62.

(30.) Baskerville A, Conlan JW, Ashworth LA, et al. Pulmonary damage caused by a protease from Legionella pneumophila. Br J Exp Pathol 1986;67:527-536.

(31.) Wong KH, Moss CW, Hochstein DH, et al. "Endotoxicity" of the Legionnaires' disease bacterium. Ann Intern Med 1979;90:624-627.

(32.) Harris LF. Legionnaires' disease associated with acute encephalomyelitis. Arch Neurol 1981;38:462-463.

(33.) Spieker S, Peterson D, Rolfs A, et al. Acute disseminated encephalomyelitis following Pontiac fever. Eur Neurol 1998;40:169-172.

RELATED ARTICLE: Key Points

* Cerebellar involvement can occur in previously healthy adults in the setting of Legionella pneumonia.

* The onset of neurologic symptoms averages 5 days after the onset of pneumonic symptoms.

* The pathophysiology is not understood at present, and deficits may persist for a prolonged period.

RELATED ARTICLE: Case Report

A 43-year-old man with no significant medical history presented with 1 week of diffuse myalgias, headache, diarrhea, and a nonproductive cough. He was a business executive and a marathon runner who denied alcohol use or toxic exposures. Two days before admission he developed fever, confusion, and shortness of breath. Upon admission he was febrile to 102.9[degrees]F with a respiratory rate of 26 breaths/min and an oxygen saturation of 93% on 3 L of [O.sub.2]. Neurologic examination at this time was within normal limits except for mild confusion. Laboratory data were as follows: white blood cell count 9.5 X 1[0.sup.3] cells/[micro]L, 89% neutrophils, sodium 124 mmol/L, creatinine 1.3 mg/dL, aspartate transaminase 392 U/L (normal, 5-40), alanine transaminase 109 U/L (normal, 5-50), and creatine phosphokinase 3,084 U/L (normal, 40-250). Chest x-ray showed infiltrates in the left upper lobe, lingula, and left lower lobe. He was administered a combination of ceftriaxone and azithromycin. Diagnostic bronchoscopy revealed hyperemic bronchial mucosa; all stains and cultures were negative. Confusion and fever gradually resolved, but on hospital Day 6 he developed slurred speech and difficulty with swallowing. Neurologic examination at this time showed an alert and oriented patient with normal strength and sensation. He had severe dysarthria, ataxia, and impaired finger-to-nose and heel-to-shin movement. Reevaluation of his laboratory data at this time showed preserved renal and liver function. Electroencephalogram (EEG), computed tomographic (CT) scan, and magnetic resonance imaging (MRI) scan of the brain were all within normal limits. Legionella urinary antigen returned positive, and he was switched to levofloxacin. A pulse of methylprednisolone was administered for presumptive treatment of an autoimmune process affecting his central nervous system, with mild improvement in his neurologic symptoms. Six months after admission, he remained with speech deficits, but his ataxia had resolved and he had resumed marathon running.

Samuel A. Shelburne, MD, Marcia A. Kielhofner, MD, and Pinky S. Tiwari, MD