European neuroborreliosis: Long term follow-up
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Lyme disease is the most common human tick borne disease in the northern hemisphere, and the southern coastline of Norway is a high endemic region regarding Lyme disease. European Lyme neuroborreliosis (LNB) often presents with a sub acute painful lymphocytic meningoradiculitis (Bannwarth syndrome) with or without paresis in the abdominal wall, the limbs or muscles innervated by cranial nerves. Central nervous system involvement as encephalitis, myelitis and vasculitis is rare. Most LNB patients experience marked improvement in neurological symptoms within weeks to a few months after antibiotic treatment, but years after treatment 10 – 50% report persisting or new symptoms including fatigue, concentration difficulties and musculoskeletal problems. Remaining complaints after adequately treated Bb infections are often named Post Lyme Disease Syndrome (PLDS). The prevalence and impact of PLDS is debated since similar symptoms are common in the general population, and there are few European controlled studies on the issue. Most studies on outcome after LNB are conducted in the US, and as Borrelia genotype and the clinical picture of Lyme disease in the US differ somewhat from what we find in Europe, the study results are not necessarily transferable to European patients. Aims Our aim was to assess the long-term impact of LNB on Health Related Quality of Life (HRQoL) in a controlled study of well-characterized adult European LNB patients. We also wanted to compare the neuropsychological (NP) functioning by assessing executive/attention functions, processing speed and memory in a group of adult LNB patients 30 months after treatment to a matched control group. Finally, we wanted to identify clinical, demographical or laboratory factors associated with a reduced HRQoL and fatigue after treatment of LNB. Patients and methods A cohort of 50 patients was followed for 30 months after treatment for LNB. The patients were recruited from a treatment study conducted in southern Norway comparing per oral doxycycline to intravenous ceftriaxone. All patients were living in the geographical region of Agder Counties, and received treatment between May 2004 and December 2007. The LNB patients brought a control person from the same geographical area, matched for age, gender and education level. Exclusion criterion for the controls was a history of acknowledged LNB. At basis pre-treatment and at 4, 12 and 30 months we did a semi structured interview, a clinical score, and spinal and blood tap. At 30 months NP functioning was assessed, and all participants completed the following questionnaires: the Fatigue Severity Scale (FSS), the Montgomery-Åsberg-Depression Rating Scale (MADRS), and the Short Form-36 (SF-36: A HRQoL questionnaire including the sum scores Mental Component Summary (MCS) and Physical Component Summary (PCS)). They were asked about previous and current coexisting diseases, psychological distress and subjective complaints. A composite clinical score made for the treatment study, summarizing subjective complaints and objective findings, was used to assess clinical status. Non-complete recovery was defined as more than 1 point score on the composite clinical score. The four NP tests in our test panel consisted of 23 subtasks, and we calculated a sumscore expressing the number of NP subtasks with the scores ≤-1 SD from the mean in the control group (range 0-23). The sumscores were then categorized into three groups: Normal: 1-5(≤-1 SD from the mean sumscore in the control group), deficit: 6-8 (>-1≤2 SD from the mean sumscore in the control group) and impairment: 9-23 (>-2 SD from the mean sumscore in the control group). In the study regarding risk factors we did a univariate analysis comparing independent demographical, clinical and laboratory data to the PCS, MCS and FSS scores to look for associations. The variables which were associated with the outcome in the univariate analyses were analyzed further in a multiple regression model. Before treatment 80 % of the patients had a complete or partial Bannwart syndrome, and 8 % had symptoms suggesting involvement of the central nervous system (myelitis, ataxia and confusion). Fifty percent were treated with oral doxycycline and 50 % with IV ceftriaxone. Sixty-eight percent were classified as definite LNB according to the criteria of the European Foundation of Neurological Society, and 32 % as possible LNB. Mean age at follow up was 55, and 58 % were male. Results Paper I: LNB treated patients had reduced HRQoL compared to controls as assessed with the SF-36 summary components PCS (P<0.001) and MCS ( p=0.010) 30 months after treatment. The patients scored lower on all the eight subscales of the SF-36, except for bodily pain. The LNB patients who reported complete recovery (56%) had similar HRQoL scores as the controls. Paper II: LNB treated patients scored lower on four NP subtasks assessing executive/attention functions, processing speed, visual and verbal memory, as compared to matched controls: Stroop test 4 (P=0.015), TMT 5 (P=0.004) Digit Symbol recall (P=0.038) and CVLT list B (P=0.003). The distribution of global NP function indicates that most of the LNB treated patients perform comparable to controls, while a small subgroup have a debilitating long-term course with cognitive impairment. Fatigue, depression, neurological deficits or HRQoL at 30 months after treatment were not associated with the global NP sum score. Eighteen out of 50 patients (36%) had objective findings in terms of neurological deficits and/or cognitive impairment. Paper III: Delayed start of treatment and remaining complaints 4 and 12 months after treatment seem to predict a worse outcome with respect to HRQoL. Delayed start f treatment, a more severe disease pre-treatment and remaining complains at 4 and 12 months after treatment seem to predict more fatigue at 30 months. Age, gender, educational level, diagnostic accuracy, treatment option, signs of infection in the central nervous pre-treatment or coexisting somatic diseases or psychological distress were not associated with HRQoL outcome 30 months after treatment in our cohort, neither were any of the assessed CSF findings before treatment or during follow-up . Conclusions 1. HRQoL was reduced in well-characterized European patients treated for LNB with a current recommended antibiotic regimen 30 months earlier, as compared to matched controls. The LNB treated patients were not more depressed and did not report more pain than the controls. Fatigue was the most disturbing persisting complaint, and was negatively associated with HRQoL. Mild neurological deficits were found in 28 % of the patients, and seemed to influence negative on the physical HRQoL and fatigue scores. The patients who reported subjective recovery had the same HRQoL as the controls. 2. Most of the patients who were treated for European LNB 30 months earlier had comparable NP functioning to matched controls, but a small subgroup had cognitive impairments regarding attention/ excecutive function, processing speed and memory that could affect their daily life. The LNB treated patients with complete recovery had similar NP functioning as the controls. We did not find any association between NP test results and HRQoL or fatigue. 3. It seems as a more serious LNB disease and a longer duration of symptoms before treatment can reduce HRQoL, and as symptom duration more than 6 weeks before treatment, a more severe disease and non-complete recovery at four and 12 months predict a higher burden of fatigue 30 months after treatment. We did not find that any laboratory data predicted outcome after treated LNB, or that any CSF finding indicated an active Bb infection 30 months after treatment. Gender, age, comorbidity, signs of pre-treatment infection of the central nervous system or CSF findings before and during follow-up were not associated with HRQoL or fatigue at 30 months. 4. Thirty months after treatment of LNB 18 out of 50 patients (36%) had objective findings in terms of neurological deficits and/or cognitive impairment.
Paper I: Acta Neurologica Scandinavica. 2011. 124(5): 349-354, Eikeland, R.; Mygland, Å.; Herlofson, K.; Ljøstad, U.; European neuroborreliosis: quality of life 30 months after treatment. Full-text not available in BORA. The published version is available at: http://dx.doi.org/10.1111/j.1600-0404.2010.01482.xPaper II: European Journal of Neurology. 2012. 19(3): 480-87, Eikeland, R.; Ljøstad, U.; Mygland, Å.; Herlofson, K.; Lohaugen, G. C., European neuroborreliosis: neuropsychological findings 30 months post-treatment. The paper is available in BORA: http://hdl.handle.net/1956/5868Paper III: Acta Neurologica Scandinavica (Early view). Eikeland, R.; Mygland, Å.; Herlofson, K.; Ljøstad, U., Risk factors for a non-favorable outcome after treated European Neuroborreliosis. The paper is available in BORA: http://hdl.handle.net/1956/5869