BRAIN INJURY, 1991, VOL. 5, NO. 1, 93-100 Case study Fever of unknown origin following traumatic brain injury R. D . J A C K S O N and W . J . M Y S I W Brain Inj Downloaded from informahealthcare.com by Chulalongkorn University on 01/08/15 For personal use only. Departments of Internal Medicine and Physical Medicine, The Ohio State University, Columbus, Ohio, USA (Received 26 October 1989; accepted 23 December 1989) Fever is a common complication of a traumatic brain injury, occurring during both the acute-care phase and the rehabilitation phase of recovery. The aetiology of fever in this population may remain obscure because of the presence of cognitive confusion associated with post-traumatic amnesia interfering with history taking and the difficult physical examination. We present a case where recovery from a traumatic brain injury was complicated by a fever of unknown origin that proved to be secondary to lateral sinus thrombophlebitis. This case emphasises the importance of a thorough knowledge of the differential diagnosis for fever that is unique to the traumatic brain injury population. Introduction One of the potential, acute complications after a severe traumatic brain injury (TBI) is fever. We have recently observed a young man with a severe TBI who developed a fever of unknown origin (FUO) that proved to be due to an unusual aetiology directly related to his recent history of central nervous system trauma. This case is presented and the differential diagnosis of fever is reviewed in the context of potential sources of fever after a severe TBI. Case report A 24-year-old, black, male, professional boxer was in excellent health prior to sustaining a technical knockout during a professional bout. He was examined at ringside and referred to the local hospital for observation. Over the ensuing 3 h, he became progressively confused and obtunded with a Glasgow Coma Scale (GCS) score of 5 and the new onset of a right pupil dilatation. A computed tomography (CT) scan of the brain confirmed a small, right, subdural haematoma with significant mass effect and a small pontine haemorrhage. Emergency surgical evacuation of his haematoma was performed and he subsequently improved his GCS score to 9 within the first 24 h post-surgery. Post-operative CT scans revealed multiple cerebral contusions and a large deficit in the region of the right posterior cerebral artery. On post-operative Day 9, the patient began to spike fevers ranging from 38 to 39.6"C. The temperature elevation was occasionallyassociated with profound diaphoresis above the mid-thoracic region and episodic hypertension that responded to intramuscular thorazine. Address correspondence to: Dr R. D. Jackson, Ohio State University Hospitals, N l l l l Doan Hall, 410 W. loth Avenue, Columbus, OH 43210, USA. 026%9052/91 S3Nl 0 1991 Taylor & Francis Ixd Brain Inj Downloaded from informahealthcare.com by Chulalongkorn University on 01/08/15 For personal use only. 94 R. D. Jackson and W .J. Mysiw Laboratory evaluation at that time included electrolytes, liver function tests, complete blood count, cultures of the blood, sputum and urine, chest radiograph, lumbar puncture and C T scan of the head; all tests were completely negative except for the presence of leukocytosis. The patient was treated with a 10-day course of trimethoprimsulpharnethoxazole with gradual defervescence of his fever and resolution of the leukocytosis. He was transferred to Dodd Hall 24h after becoming afebrile for comprehensive rehabilitation of his residual physical, cognitive and behavioural deficits. Within 24 h of transfer, the patient's temperature again rose to 38.5"C. Physical examination revealed a cachectic, black male weighing 50 kg. Vital signs revealed a regular pulse of 100 beats per minute, a respiratory rate of 35 per min and a blood pressure of 120/60mmHg. During the course of the physical examination, the patient became diaphoretic with an elevation in his pulse to 110 beats per minute and an increase of the blood pressure to 134/90 mmHg; this episode resolved spontaneously within 30 min of onset. There was no evidence ofskin lesions or adenopathy. The tympanic membranes were normal. Dentition was good and there was no evidence of a pharyngeal abscess. The chest examination was remarkable for a few scattered ronchi in the right lower lobe. The abdominal examination was normal. The neurological examination was stable with persistent four-extremity weakness, no evidence of papilloedema and no evidence of purposeful responses to commands. Laboratory studies revealed a mild, normochromic, normocytic anaemia with a white blood cell count of 15 500 cells/mm3. Electrolytes, liver function tests and arterial blood gases were all normal. A lumbar puncture was performed and was unremarkable except for an elevated protein of 57 mg/dl (normal <50 mg/dl). Cultures of the urine, sputum, blood and cerebral spinal fluid (CSF) were all negative. A chest radiograph was suggestive of an early, right, middle-lobe infiltrate, prompting the initiation of a 10-day course of intravenous penicillin (2 x lo6 units/day) and gentamicin (75 mg/8 h). O n this scheme, the patient defervesced over 72 h. One day after discontinuation of the antibiotics (post-operative Day 44),the patient became diaphoretic proximal to the mid-thoracic region, mildly hypertensive and febrile to 39°C. The physical examination was unchanged. Laboratory evaluation revealed a white blood cell count of 22 OOO cells/mm3. In addition, liver function tests were slightly elevated with an alkaline phosphatase of 17Opgll (normal <95pg/l), an ALT of 55pg/l (normal < 40 pg/l) and an AST of 122pg/l (normal <60 pg/l). Connective-tissue serology and viral titres were negative. Cultures of the blood, urine and CSF were again negative as were bone marrow cultures. The lumbar puncture remained normal except for the elevated CSF protein, which was now further elevated to 116 mg/dl. Chest radiography, sinus films, an upper GI with small bowel follow-through, abdominal CT scan, abdominal ultrasound, a ventilation-perfusion lung scan and a 2-D echocardiogram were also normal. An intravenous pyelogram (IVP) was suggestive of deviation of the right ureter. An indiumlabelled white blood cell scan revealed a single focus of intense uptake in the right occipital area. Subsequent studies, attempting to focus on the area of inflammation that was noted in the white blood cell scan, included a head CT scan and bone scan, which failed to confirm any localized abnormalities. The EEG revealed right-delta activity with marked slowing. Magnetic resonance imaging (MRI), however, demonstrated an absence offlow in the right lateral venous sinus with intense signals surrounding this sinus, compatible with an inflammatory process (figure 1). Arteriography of the right internal carotid system, with prolonged filming for better demonstration of the venous phase, demonstrated normal cortical veins with opacification of the saggital sinus, right lateral sinus and jugular venous system compatible with thrombosis. Brain Inj Downloaded from informahealthcare.com by Chulalongkorn University on 01/08/15 For personal use only. Fever of unknown origin and TBZ 95 Figure 1 . Magnetic resonance imaging of the brain in a young male boxer with fever of unknown origin complicating a traumatic brain injury. Despite the motion in the scan, the arrow depicts inj?ammation in the region of the transverse sinus, suggestive of lateral sinus thrombophlebitis. Based on these results, the diagnosis of right-lateral sinus septic thrombophlebitis (LST) was made. The patient was treated over a &week course with parented penicillin and metronidazole. Repeat white blood cell scans, performed 3 weeks after initiation of antibiotic therapy and 1week after discontinuation of antibiotic therapy, were both normal. Clinically, the patient defervesced within several days of initiating this last antibiotic scheme and remained afebrile after its discontinuation. O n completion of his 3-month rehabilitation stay, the patient was transferred to a nursing home with continued significant cognitive deficits and tetraplegia, and was dependent for most aspects ofhis care, but with no evidence of recurrent fever. Discussion The clinical course described in this case fits the classic definition of fever of unknown origin (FUO), which requires (a) a temperature elevation greater than 38.2"C on several occasions over at least a 3-week period of time and (b) inability to diagnose the underlying aetiology after at least 1week ofintensive investigation [l].Disease entities commonly associated with an FUO include infectious, neoplastic, autoimmune, granulomatous, metabolic, inherited, psychogenic, periodic and thermoregulatory disorders [11. The potential aetiologies for fever following TBI in an otherwise healthy adult, however, are more limited and should be used to guide the initial investigation. Brain Inj Downloaded from informahealthcare.com by Chulalongkorn University on 01/08/15 For personal use only. 96 R . D.Jackson and W.3. Mysiw Urinary tract infections affect approximately 40% of TBI patients during the rehabilitation phase of their recovery [2]. Other potential genito-urinary sources of prolonged fever include pyelonephritis, perinephric abscess and prostatic abscess [ 11. Ureteral obstruction, seen in approximately 1% of patients post-TBI [2], is also an uncommon cause of fever. Repeated urine cultures, the absence of pyuria and an intensive evaluation including IVP, renal ultrasound and an abdominal CT scan failed to show any signs of a genito-urinary aetiology in our patient. Respiratory problems affect 34% of patients after a traumatic brain injury and predispose the patient to pulmonary infections [2]. Fifteen per cent of patients have been noted to develop pneumonia during their acute hospitalization and rehabilitation course. The risk in the TBI patient is accentuated by the presence of nasogastric tubes, which increases the probability of aspiration by as much as 25% [3,4]. In addition, the presence of an endotracheal or tracheostomy tube predisposes the patient to bacterial colonization and a greater risk of secondary lung infections [5]. Poor ventilation with secondary obstructive atelectasis and the collapse of pulmonary alveolus is estimated to be the most common pulmonary complication of trauma and maybe a forerunner of pneumonia following trauma [4]. In addition, tissue necrosis secondary to trauma to the lung at the time of the TBI with formation of a pulmonary cavity may also predispose to secondary lung infections [6]. During the mid-portion of our patient’s hospital course, he showed evidence of a right middle-lobe infiltrate, and the diagnosis of recurrent aspiration pneumonia was entertained. However, the recurrence of fever immediately after cessation of antibiotics and the multiple normal chest radiographs caused continued investigation for the aetiology of his persistent fever. Paranasal sinusitis has increasingly been recognized as a source of fever in trauma patients. The incidences of sinusitus after nasotracheal intubation has been estimated as high as 26% [7]. Nasogastric intubation causes an additional but slightly less prominent risk for sinusitis and fever in the trauma patient [8]. Sinus films, including Water’s view of the paranasal sinuses, have been recommended to be sufficiently specific to make the diagnoses ofsinusitisin up to 90% ofpatients [9]. Investigations ofour patient with sinus films revealed no evidence of sinusitis, an important consideration regarding his eventual diagnosis of lateral sinus thrombophlebitis. An additional cause of fever occurring from the nasopharyngeal cavity is dental infection. Abscess formation has been described in teeth rendered non-viable from multiple aetiologies [lo], including facial trauma. Cardiovascular aetiologies of fever include both acute and subacute endocarditis [ 111 and dissecting aortic aneurysm [12]. Intravenous line sepsis is a common cause offever in the neurosurgical literature [131. However, negative blood cultures, normal chest radiographs and a normal 2-D electrocardiogram, as well as an unremarkable physical examination, lowered our suspicions of a cardiovascular aetiology for fever. Thromboembolic disease is a common complication in the trauma patient who has multiple risk factors that predispose him for the development of deep venous thrombosis and pulmonary embolus [14]. Four per cent of patients with TBI have been reported to develop thrombophlebitis during their rehabilitation course and 75% of these patients suffered a concommitant non-fatal pulmonary embolus. This particular report of incidence, however, may well be excessively low as diagnostic studies were only pursued when clinical manifestations were present, yet the usual signs and symptoms of pulmonary embolus are relatively non-specific and difficult to discern in the cognitively impaired TBI patient. Because of our concerns that prolonged immobilization and post-operative status could contribute to a hypercoaguable state that would predispose our patient to thromboembolic Brain Inj Downloaded from informahealthcare.com by Chulalongkorn University on 01/08/15 For personal use only. Fever of unknown origin and TBI 97 disease, a ventilation-perfusion lung scan was performed and was completely normal with no evidence of ventilation or perfusion defects. Heterotopic ossification (HO) has been known to minic deep venous thrombosis in its presentation with fever [15]. HO is an extremely common complication of traumatic brain injury ranging in incidence from 11 to 80% of patients [16]. Other musculoskeletal disorders may also be potential causes of fever in a patient with TBI. Osteomyelitis, from haematogenous or contiguous spread, should be aggressively pursued [2]. The bone scan, however, in our patient was entirely normal, making osteomyelitis or heterotopic ossification unlikely. Cryptic haematomas, particularly in the perisplenic, pericardial and retroperitoneal areas, have all been associated with prolonged fever after remote trauma [2]. Other intraabdominal aetiologies of fever include trauma to the viscera with secondary abscess formation commonly related to injuries of the spleen, small intestine and liver [17]. Perirectal abscess formation, secondary to bowel programmes requiring manual rectal stimulation, also warrants consideration as a possible source of fever. The gastrointestinal radiographic studies, abdominal C T scan and white cell scan performed in our patient should have helped to define any intra-abdominal mass requiring further medical evaluation. Adverse drug reactions are also known to cause fever [18]. An important example of drug fever in patients with TBI is the malignant neuroleptic syndrome. Out of all users of major tranquillizers, 1.5% have been noted to have marked elevation in temperature [19]. Our patient had not received neuroleptic medication during his hospitalization and all medications were discontinued on a short-term basis to exclude them as a cause for his fever. Finally, neurological aetiologiesfor fever warrant consideration after a TBI based on the contribution of both the underlying trauma and subsequent neurosurgical intervention. Uncomplicated wound infections that do not involve deep tissues or brain parenchyma are usually readily observable, making the diagnosis straightforward [13]. Post-operative bacterial meningitis is an infrequent complication of neurosurgical procedures, but is more commonly associated with open head injuries [20]. The lumbar puncture is fairly diagnostic in this syndrome and cultures should be used to guide the specific antimicrobial therapy. Infected intraventricar shunts [21], hyperthermic reactions to acute hydrocephalus [223 and neurogenic hyperthermia [23] have also been reported as unusual causes of fever. Fever may also be associated with seizure activity in adults in the absence of CNS inflammatory diseases. Fevers usually occur within 48 h of the seizures but the temperature rapidly returns to normal. However, fever has also been reported as a manifestation of partial complex seizures where minimal signs and symptoms of seizure activity can confuse the diagnosis ~41. Owing to a high index of suspicion of the CNS as the aetiology of fever in our patient, and the persistent evidence of an elevated protein in the CSF, repeated investigations of the CNS were undertaken. Multiple head C T scans showed only evidence of cerebral infarcts associated with his TBI, as the lesion that was responsible for his elevated temperature rested in a relative blind spot for computed tomography [25]. The diagnosis was initially suggested by a white blood cell scan, which revealed intense focal uptake over the right occipital region. Further localization studies included a negative bone scan, which excluded osteomyelitis of the occipital bone, and MRI, which revealed increased signal in the region of the lateral sinus consistent with inflammation. MRI offered the solution because of its superior resolution of posterior structurs and clear demonstrations of flow through vessels [25]. In our case, the absence of flow with the suggestion of inflammation in the right lateral dural sinus led us to the diagnosis of lateral sinus thrombosis (LST). The diagnosis was R . D. Jackson and W .J . Mysiw Brain Inj Downloaded from informahealthcare.com by Chulalongkorn University on 01/08/15 For personal use only. 98 confirmed with arteriography, which has been considered the definitive study for the diagnosis of LST [26,27]. Lateral (transverse) sinus thrombophlebitis has become an obscure aetiology of fever in the modern antibiotic era (27). The development of LST almost always follows acute or chronic otitis media, mastoiditis or cholesteatoma formation and is due to haematogenous or contiguous spread [26]. Uncommonly, LST has also been reported to occur secondary to trauma [28,29], although most causes of post-traumatic LST are associated with aseptic thrombosis. The diagnosis of LST can be difficult as there is no one pathognomonic sign or ideal test for recognizing this entity [27]. The clinical picture of septic lateral sinus thrombophlebitis typically consists of fever, neck pain and stiffness and varying degrees of lethargy progressing to coma [27]. Focal neurological signs and papilloedema can be seen in up to 50% ofpatients with LST [27,29]. Evaluation of the cerebrospinal fluid is non-specific with usual findings including normal opening pressures, variable glucose levels, elevated protein concentrations and negative cultures [27,29]. The initial recognition of this entity in our patient was obscured by his impaired cognitive status, which precluded obtaining an appropriate history, and the physical examination, which failed to demonstrate papilloedema or other focal neurological signs not attributable to his TBI. The lumbar puncture, however, was consistent with LST with persistent elevation of the CSF protein. Treatment of lateral sinus thrombophlebitis has been the subject of controversy [27,29,30]. Current recommendations for septic LST include medical management with antibiotics combined with surgical intervention where appropriate [30]. Our patient was started on penicillin and metronidazole, but was not deemed to be a good surgical risk because of his debilitated condition, previous surgery and religious belief, which would prevent administration of blood products. It was also believed that he would not benefit from exposure of the mastoid sinus and debridement since it appeared that the mastoid sinus was radiographically normal and free of infection. There is no evidence that the septic LST in our patient arose from mastoiditis or otitis media. We believe that the thrombosis formed secondary to endothelial damage and subsequently became infected during a transient septic episode. Following motor vehicle accidents, dural sinus thrombosis can be caused by endothelial damage and intramural haemorrhage of the sinus wall. O u r patient was subjected to repeated blows to the head in professional bouts, which could result in endothelial damage from similar accelerationdeceleration forces. Summary In summary, we feel this case illustrates the difficulty in determining the aetiology offever in a young male recovering from severe traumatic brain injury. Because of the relative lack of specific symptoms and the confusing signs seen in the TBI patient during post-traumatic amnesia, rapid recognition of diseases such as lateral sinus thrombophlebitis and other unusual aetiologies of fever after traumatic brain injury are contingent on a thorough knowledge of the differential diagnosis of fever in this population. Careful discriminate use of appropriate laboratory tests may speed diagnosis and eventual recovery in these individuals. References 1. PETERSDORF, R. R.: Chills and Fever. In R. G. Petersdorf, R. D. Adams, E. Braunwald et 01. (Eds) Harrison’s Principle of Internal Medicine (10th edn) (McGraw-Hill, New York), pp. 57-65, 1983. Fever of unknown origin and TBI 99 Brain Inj Downloaded from informahealthcare.com by Chulalongkorn University on 01/08/15 For personal use only. 2. KALISKY,Z., MORRISON, D. P., MEYERS, C. A. and VON LAUFEN, A.: Medical problems encountered during rehabilitation of patients with head injury. Archives ofphysical Medicine and Rehabilitation, 66: 25-29, 1985. D. E.: Nosocomial pneumonia: new concept on an old disease. Infection Control and 3. CRAVEN, Hospital Epidemiology, 9: 57-58, 1988. C., and PULLIAM, M.: Problems associated with multiple trauma. In J. R. Yooman (Ed) 4. W A ~ S Neurological Surgery (2nd edn) (W. B. Saunders Company, Philadelphia), pp. 2475-2530, 1982. J.: Hospital-acquired pneumonia. In P. R. Wenzel (Ed.) Prevention and Control of 5. 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G., TOTH-DARU, P., JANAKY, J. et al.: Indomethacin is effective against neurogenic 23. BENEDICT, hyperthermia following cranial trauma or brain injury. CanadianJournal of Neurological Sciences, 14: 145-148, 1987. 24. SEMEL, J. D.: Complex partial status epilepticuspresenting as fever ofunknown origin. Archives of Internal Medicine, 147: 1571-1572, 1987. R. C., HOLLAND, G. N., MOORE,W. J. and WORTHINGTON, B. S.: Nuclear magnetic 25. HAWKES, resonance (NMR) tomography of the brain: a preliminary clinical assessment with demonstration of pathology. Journal of Computer-Assisted Tomography, 8: 577-586, 1980. F. S. and SWARTZ, M. N.: Inflammatory thrombosis of major dural venous sinuses 26. SOUTHWICK, and cortical veins. In R. H. Wilkins and S. S. Rengachary (Eds) Neurosurgery (McGraw-Hill, New York), pp. 19561961, 1985. J. H., TEICHGRAEBER, J. F. and TURNER, J. S.: Lateral sinus thrombosis: a modem 27. PER-LEE, prospective. 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