Adult Hemophagocytic Lymphohistiocytosis (HLH) with Neurological Involvement: Diagnostic Complexities – A Case Report and Literature Review

Introduction

Differential diagnosis of diseases presenting as a non-specific clinical picture involving the CNS (central nervous system) may be challenging and can delay the therapeutic process. hemophagocytic lymphohistiocytosis (HLH) is a rare disease that can manifest with neurological dysfunction. It is a potentially fatal disease of normal but overactive histiocytes and lymphocytes, which commonly appears in infancy, although it has been reported in all age groups. It is characterized by proinflammatory overactivity of the immune system, with decreased or absent function of NK cells and increased cytotoxic T-cell activation and expansion, with resulting overactivity of proinflammatory cytokines (interferon gamma, tumor necrosis factor-α, and granulocyte-macrophage colony-stimulating factor). In infants it is usually primary and hereditary, whereas in adults HLH is usually secondary to infection, malignancies, or autoimmune diseases [1,2]. Systemic symptoms such as fever, hepatosplenomegaly, pancytopenia, lymphadenopathy, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis are typical for HLH. CNS involvement is more commonly observed among pediatric patients than in adults [2]. We present a case of a 54-year-old man in whom HLH had been diagnosed, manifesting mainly as neurological signs, masking demyelinating diseases of the CNS.

We report the case of a patient with CNS involvement in the course of HLH. The primary outcome of literature analysis was to identify and summarize specific clinical features and outcomes in patients with HLH complicated by neurological signs. To identify appropriate literature, a systematic literature search was conducted based on the PRISMA guidelines [3]. The electronic databases PubMed, Scopus, Embase, and Google Scholar were searched for all clinical case reports or case series descriptions or original articles about HLH presenting with neurological signs, published before 30 November 2024. The studies were published in English or Polish. The following keywords or MeSH including all commonly used abbreviations of these terms were used: “hemophagocytic lymphohistiocytosis,” “secondary HLH,” “neurological signs,” “neurological manifestation,” “neurological manifestations,” “CNS involvement,” “HLH,” CNS.” We used the “AND” operator in each case. For this analysis, we included research studies, reviews, and case reports containing neurological manifestations associated with HLH. Most of the review papers contained compiled case reports. The search, based on the titles and abstracts of all reports identified through electronic databases, was conducted by 2 reviewers independently to identify the studies matching the assumed criteria. In case of uncertainty, the full text of the article was obtained and discussed. Initially, 183 results were obtained, without setting a time criterion. They came from the years 1983–2024. After setting the time criterion to 10 years (2014–2024), 117 articles were selected. In the next round, we discarded papers that were abstracts, editorials, or letters to the editor, leaving 104 full-text papers. Subsequently, duplicate articles in the analyzed databases were discarded, thus obtaining 87 articles. Then, the titles and abstracts of all articles were analyzed, discarding thematically unrelated articles or those on other disease entities. We found 37 cases of HLH associated with neurological signs in 30 articles, and these were included in the analysis and are presented in the Discussion section. The flowchart showing the process of selecting publications for review is shown in Figure 1.

Case Report

A 54-year-old man, without chronic diseases, was admitted to the Department of Neurology due to spastic paraparesis with sphincter disorder increasing for about 3 months. He reported having weakness, paresthesia and numbing of the lower limbs, urinary incontinence, sexual dysfunction, and impaired visual acuity. A neurological examination showed vertical nystagmus, spastic paraparesis (MRC 1,1,2 in the left lower limb; MRC 2,3,3 in right lower limb) and mild paresis of the upper limbs (MRC 4,4,4 on both sides), and decreased superficial sensation in the lower limbs, distal to the knees, with greater intensity on the left side. Latency of potential P100 in visual evoked potentials was prolonged bilaterally. In the beginning, we suspected neuromyelitis optica spectrum disorders (NMOSD). He also had a fever of unestablished etiology for about 1 year. For this reason, 8 months prior to admission to the Neurology Clinic, a bone marrow biopsy was performed, which showed only reactive changes.

On brain MRI, there were multiple disseminated focal lesions hyperintensive in T2-weighted and FLAIR images in the white matter of both cerebral hemispheres and in the corpus callosum; 2 lesions enhanced with contrast located next to the posterior corner of the left lateral ventricle and subcortical in the right occipital lobe; and no pathology of optic nerves was found (Figure 2).

On thoracic MRI, there were demyelinating lesions on the left side of the spinal cord at the level Th5–Th6 (2.6 mm), Th10–Th11 (3 mm), and Th12-L1 (4.5 mm), without contrast enhancement (Figure 3). Cerebrospinal fluid (CSF) showed mildly increased cytosis (18 cells/μl) and increased protein level (97 mg/dl). Neuroinfection was excluded. Antibodies against aquaporin 4 and myelin oligodendrocyte glycoprotein were negative in the serum. Progressive multifocal leukoencephalopathy was also considered, as antibodies against John Cunningham virus were positive in the serum, but the viral DNA was negative in the CSF. Although elevated level of CRP (>200 mg/l) and fever were observed, no source of infection was found and all cultures were negative. Tuberculosis was excluded. Antibiotics treatment was not effective.

The patient was treated intravenously with methylprednisolone in a total dose of 8 g, without improvement. One procedure of plasma exchange was performed, with improvement in his neurological condition (improvement of lower-limbs strength), but he was disqualified from further plasma exchanges because of fever and increased CRP level. Intravenous immunoglobulins were considered as an alternative treatment, but as his general condition was not stable, with increase of inflammatory markers in the blood, it was not used.

Computed tomography (CT) of the chest, abdomen, and pelvis revealed hepatomegaly, enlarged to 9-mm lymph nodes of mediastinum and lung hilum, and a small quantity of fluid in the pleural cavity. No neoplasms were found.

Control brain MRI showed enlargement of lesions compared to the previous examination (Figure 4). CSF flow cytometry did not show brain lymphoma. Oligoclonal bands type 4 were identified in the CSF (ie, present in the serum and in the CSF), indicating disruption of the blood-brain barrier.

During the patient’s stay in the Neurology Clinic, his neurological condition did not improve. He also had fever, with irregular increase in temperature, with a peak of 40.5°C. Later, due to persistent fever of unknown etiology, he was transferred to the Hematology Department, where further diagnostics established the final diagnosis of HLH – the HLH-2004 diagnostic criteria were met (5/8 points), the HScore was 224 points, and the probability was 96–98%.

The patient had fever, hepatomegaly, cytopenias affecting 2 lineages in the peripheral blood, marked hyperferritinemia (4037 μg/l), and hyperglyceridemia (403 mg/dl). In the Hematology Department, additional tests were conducted, which did not identify an immunological, infectious, or neoplastic basis for HLH.

The patient was qualified for treatment with the HLH-94 protocol, using dexamethasone, etoposide, cyclosporine A, and intrathecal methotrexate, and physical rehabilitation was continued.

The patient remained under the care of hematologists, who did not perform follow-up MRI scans or cerebrospinal fluid analysis, as the obtained results would not affect the patient’s further diagnostic or therapeutic management in any way.

During the first 6 months, there were significant improvement in the patient’s general condition and neurological symptoms (decrease of lower-limb paresis and slight improvement in sphincter function), defervescence, normalization of body temperature, and CRP level.

After a short, temporary improvement in the patient’s condition, the disease gradually progressed and the disability became more severe. The quadriparesis worsened and the patient remained bedridden and catheterized. About 18 months after the diagnosis of HLH, the patient died.

Discussion

HLH is a multisystemic inflammatory disease with a severe course. Its signs develop as a consequence of prolonged and ineffective activation of the immune system. It has 2 forms – primary or familial (FHL), and secondary (sporadic). FHL is a consequence of biallelic mutation in genes that take part in the secretion pathway of exocytosis dependent on lysosomes, and occurs in infants [4–6]. These mutations primarily include the PRF1 and UNC13D genes [7]. FHL in children is often has CNS involvement as the first presenting feature [7–10]. Secondary or acquired HLH occurs more commonly in older children and in adults and is associated with infections, malignancies, rheumatoid diseases, chemotherapy, or organ transplantation [4,6]. The most common infectious factor that triggers secondary HLH is Epstein-Barr virus, causing HLH mainly in children and teenagers. The most common causes of HLH in adults are malignant neoplasms, observed in 45% of adult cases, among which, hematological malignancies dominate [6,11]. When associated with rheumatic diseases, secondary HLH is referred to as macrophage activation syndrome, which is a dangerous and life-threatening complication of systemic inflammatory disorders [4]. HLH can lead to severe complications, including sepsis, bleeding, and multiorgan failure. The North American Consortium for Histiocytosis proposed new concepts to facilitate the diagnosis and treatment of HLH. HLH subtypes should be categorized according to their etiology: familial, rheumatologic, malignancy-associated, and HLH disease mimics [5].

CNS involvement frequently occurs in pediatric patients, leading to seizures, meningismus, peripheral neuropathy, cranial nerves involvement, ataxia, mental status changes, encephalopathy, and coma [6,12]. Table 1 summarizes clinical data of patients from case reports of HLH with neurological manifestations [1,2,7–35].

Diagnosis of HLH is difficult because the atypical clinical picture can mimic other serious disorders, including sepsis. HLH-2004 provides the basic diagnostic criteria for HLH, which are also used to monitor the disease:

The other diagnostic tool is the HLH-probability calculator (HScore), with graded clinical and laboratory parameters like immunosuppression, fever, organomegaly, hypertriglyceridemia, ferritin, aspartate aminotransferase, fibrinogen, presence of cytopenia, and hemophagocytosis in bone marrow aspirate [6].

Symptoms of HLH are non-specific. Our patient had persistent fever and elevated markers of inflammation in the blood, together with neurological signs and pathological results of MRI and CSF analysis. The CNS is affected in 10–73% of patients with a diagnosis of HLH, usually at the time of diagnosis. It is associated with worse prognosis and increased mortality [6,37]. A cohort study showed that the most common neurological sign in children is seizures. Mental status changes may occur, suggesting involvement of the grey matter [38]. Neurological signs observed in our patient required differential diagnostics with MS and NMOSD, and additional studies excluded these demyelinating diseases of the CNS. In 16–76% of HLH cases, there are abnormal CSF results: 10–47% of patients have pleocytosis, and 11–41% have high levels of protein [36]. Similar findings were present in the CSF of our patient. Also, in the case report presented by Pan et al, the analysis of CSF of a 10-month-old patient diagnosed with EBV-triggered HLH showed protein 3.5 g/l and pleocytosis 20×109/l [13]. Neurological signs and pathological results of the CSF are negative prognostic factors that decrease the 5-year-survival rate from 67% to 40% [12,37].

In case of neurological symptoms on brain MRI of patients with HLH, there are usually large, multifocal, bilateral, and confluencing lesions hyperintensive in T2-weighted images, especially in FHL, and hemorrhages can also occur [38]. In our patient, on MRI there were lesions described as demyelinating in the brain and spinal cord. Drago et al published a case report of a young girl diagnosed with HLH with neurological symptoms, and a follow-up brain MRI revealed an isolated glial area of white matter in the left centrum semiovale. The examination was performed after treatment with high doses of steroids and immunoglobulins. Previously, she had symptoms of irritability and lethargy, and an encephalogram showed encephalitis. During dose reduction, she had an episode of palpebral ptosis, which resolved spontaneously, with no evidence of new changes on brain MRI [14]. Woodward et al described a case of a 59-year-old woman with hemorrhagic encephalomyelitis with spinal subarachnoid hemorrhage in HLH, although there was no CNS tissue biopsy that would provide 100% diagnostic certainty. The patient reported confusion and bilateral lower-extremity weakness. Examination revealed mental status fluctuations, severe abulia, and paraparesis, which rapidly progressed to flaccid paraplegia with a thoracic sensory level. A brain MRI showed trace intraventricular hemorrhage and sulcal hyperintensity, while MRI of the spine showed non-compressive SAH at the T6–T10 level. There was also cord signal abnormality extending from T5 to T8, with subtle enhancement of the cauda equina. Continuous electroencephalogram monitoring showed diffuse slowing consistent with encephalopathy [15]. Other case reports included a 17-year-old with bilateral paraparesis who was found to have both a compressive intrathecal lesion at the level of T12-L1, and T6–9 syringohydromyelia. Biopsy of this compression lesion revealed a blood clot in the intradural space. HLH was diagnosed based on a biopsy of the spinal nerve root [16,17]. A case of nerve root involvement in an adult, observed during autopsy, has also been reported, but with no cord involvement [15,17]. Algahtani et al reported a case with MRI images similar to those of our patient. They described multiple demyelinating lesions in both cerebral hemispheres (mostly involving the parietal and occipital lobes), corpus callosum, cerebellar hemispheres, and dorsal pons [23].

There are few detailed case reports of adults with HLH and CNS symptoms. Sakaguchi et al analyzed 36 available descriptions of such clinical cases. Of the 25 cases where CSF data were available, 48% had no increase in CSF cell counts. In 32 cases, the results of imaging tests were available – 31% of them showed no abnormalities in MRI or CT scan of the head, despite the presence of CNS symptoms [39].

Differential diagnosis of HLH with CNS involvement includes acute disseminated encephalomyelitis, acute necrotizing encephalopathy, vasculitis of the CNS, MS, and viral encephalitis [39]. Some of these diseases have characteristic features that may help in the differential diagnosis, and which can be assessed using imaging or laboratory tests.

Rasmussen’s encephalitis usually affects only 1 hemisphere. In acute necrotizing encephalopathy, there is usually symmetrical necrosis of the thalamus, and there are no extensive changes in the white matter. Cerebral calcifications are more typical of interferonopathy. However, epilepsy associated with febrile infection is poorly characterized and in some patients is a manifestation of undiagnosed HLH [10].

In almost all the published case reports we found, the patients presented to hospitals with neurological symptoms of unknown cause, which were subject to further diagnosis. In some of them [26,32], neurological symptoms developed only during hospitalization. In most, there was suspicion of aseptic encephalitis. Demyelinating processes were included in the differential diagnosis in only 3 cases [15,19,23]. The strongest suspicion of a demyelinating process, and thus most similar to the present case, was reported by Algahtani et al [23].

In the management of this case there were 5 strategic steps: control of hyperinflammation, clearance of activated immune cells, treatment of infectious factors with antimicrobial agents, substitution of immune system with allogeneic hematopoietic stem cell transplant (HSCT) in primary or resistant/recurrent HLH, and supportive treatment with prophylactic antimicrobial agents and transfusions [36–45].

Conclusions

HLH continues to be a serious medical problem because of its high mortality rate and therapeutic difficulties. Rapid diagnosis and administration of treatment can prevent death of a patient. In case of neurological involvement, differential diagnosis is necessary. Increased clinical awareness of HLH should be present in a non-specific course of various diseases, because proper treatment of HLH improves prognosis and outcome.