Hemichoreo‐hemibalism as a Manifestation of Central Nervous System Chronic Graft‐versus‐Host Disease

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Hematopoietic stem cell transplantation (HSCT) is an effective treatment modality for many life‐threatening diseases that were once considered incurable.1, 2 This therapy has evolved rapidly during the last few decades due to immunologic advances and progress in stem cell technology; currently, more than 60,000 HSCTs are carried out annually worldwide.2 In the first few years of using this therapy, patients survived only for a few months, despite successful grafts and remissions of the malignancies, due to complications that arose soon after transplantation, including severe bleeding or severe infections caused by thrombocytopenia or neutropenia, respectively.2

Recently, transplantation‐related mortality soon after transplantation decreased because of the introduction of reduced‐intensity conditioning regimens and more effective anti‐infectious agents.3, 4 Unfortunately, complications arising a longer period after transplantation, such as graft‐versus‐host disease (GVHD), has begun to emerge. These are even more problematic than early onset complications, because poor progress has been made in decreasing late transplantation‐related mortalities.3 Here, we report a case of chronic GVHD (cGVHD) of the central nervous system (CNS) presenting as hemichorea‐hemiballismus.

Case Report

A 45‐year‐old woman with acute myelogenous leukemia underwent total body irradiation (13.2 Gy) and chemotherapy while awaiting an HLA‐haploidentical (5 of 10 compatible alleles) HSCT from her daughter. The transplant was performed with no complications, and she continued post‐transplantation cyclophosphamide and fludarabine to facilitate a successful graft. At 104 days post‐transplantation, the patient presented with a red and itchy eye and jaundice but no skin rash or diarrhea. She was diagnosed with ocular and hepatic GVHD Type 1; methylprednisolone was initiated, and she achieved complete remission.

The patient continued immunosuppressant therapy with prednisolone, and the dose was tapered until Day 219 post‐transplantation, at which point the hematologist decided to suspend it, because there was no recurrence of GVHD, and the probability of a later recurrence was low.

On Day 253 post‐transplantation, the patient was admitted to the emergency room with new‐onset, right, involuntary, choreic movements in the distal upper limb associated with flailing and ballistic movements of the right side of the body with no other symptoms (Video S1). A brain magnetic resonance image (MRI) was obtained and, on a fluid‐attenuated inversion recovery (FLAIR) sequence, revealed a focal lesion in the right occipital lobe and a lesion in the left globus pallidus. The imaging study did not show any evidence of subthalamic compromise (Fig. 1A,B). Cerebrospinal fluid (CSF) analysis was normal (0 leukocytes; 0 red blood cells; glucose. 50 mg/dL; proteins, 35 mg/dL; Indian ink, potassium hydroxide, Gram, and latex for capsular antigens were negative). Haloperidol and clonazepam were initiated with improvement of symptoms, and the patient was discharged.

Figure 1.

Brain MRIs. (A) An initial brain MRI in a coronal T2‐weighted sequence that does not evidence subthalamic compromise. (B) An initial brain MRI in an axial FLAIR sequence reveals a right leptomeningeal, focal, nodular and parenchymatous, cortico‐subcortical occipital, hyperintense lesion (arrow) and another focal hyperintensity located in the left globus pallidus (arrowhead). (C) A follow‐up brain MRI in a coronal T2‐weighted sequence reveals a focal, hyperintense lesion in the left subthalamic nuclei (arrow). (D) A follow‐up brain MRI in an axial FLAIR sequence has evidence of a decrease in size in the right focal, nodular and parenchymatous, cortico‐subcortical occipital, hyperintense lesion (arrow); There is also evident increased intensity in the lesion located in the left globus pallidus (arrowheads).

Fifteen days later, the patient had a deterioration of symptoms and was once again admitted to the emergency room, where high‐dose prednisone was initiated and led to improvements in her choreic movements. Because of uncertainty regarding the etiology of these lesions, however, a stereotactic brain biopsy was performed to establish their cause and to eliminate any possibility of neuroinfection or acute myelogenous leukemia recurrence.

The stereotactic biopsy was obtained from the right occipital lesion. The histopathology results revealed an extensive vascular, perivascular, and parenchymatous mononuclear infiltrate with a predominance of CD8‐predominant T cells (T‐cell/CD8+ lymphocytes) (Fig. 2), with no evidence of blasts or malignant cells and or of microorganisms in periodic acid–Schiff, BK, Gomori, or Whartin Starry stains. Immunohistochemistry was negative for herpes simplex virus Type I, cytomegalovirus, and Toxoplasma gondii. To establish the presence of donor T cells, we performed a short‐tandem‐repeat assay on the brain tissue sample, which revealed a T‐cell mixed chimerism, suggesting infiltration by allogeneic donor lymphocytes.5 A diagnosis of CNS cGVHD was established, and treatment was initiated with corticosteroids, amantadine, and risperidone. A follow‐up brain MRI at 7 months after the onset of the movement disorder (Fig. 1C,D) revealed a smaller, focal lesion in the right occipital lobe and a more hypertense lesion in the left globus pallidus, now evidencing left subthalamic compromise.

Figure 2.

Histopathologic findings from brain biopsy. Severe, multifocal infiltration of mononuclear inflammatory cells involved in the vascular, perivascular and parenchyma compromise (hematoxylin and eosin [H&E]). The predominant infiltrating cells are CD5+ T lymphocytes, and the most common immunophenotype is CD8+ T lymphocytes. There are CD68+ macrophages and microglia and fewer CD20+ B lymphocytes. The studied cells were negative for myeloperoxidase, CD34, and CD117. There was no evidence of blast cells or other neoplastic cells or of microorganisms in the special stains periodic acid–Schiff, BK, Gomori, and Whartin Starry. Immunohistochemistry was negative for herpes simplex virus I, cytomegalovirus, Epstein‐Barr virus, and Toxopasma gondii.

Discussion

cGVHD is an immune‐mediated disorder that occurs >100 days after transplantation.3, 6, 7 It presents in 30% to 50% of patients who undergo transplantation and in 60% to 70% of transplantations from unrelated donors.8 It is presumed to occur when immune cells, particularly T‐cell lymphocytes, transplanted from a nonidentical donor recognize the transplantation recipient as foreign, and the host thymus is incapable of deleting them.3, 9 Clinically, it can compromise skin, oral mucosa, lungs, and the gastrointestinal tract and liver; however, all organ systems are at risk.6, 8, 9 Few cases of neurologic involvement have been reported, and they mainly initiate with compromise of the peripheral nervous system (myasthenia gravis, inflammatory myopathies, peripheral neuropathy) but can also manifest with compromise in the CNS (a vasculitis‐like manifestation, demyelination, or an encephalitis‐like disease).6, 8, 9, 10

CNS involvement in cGVHD is uncommon. To date, few cases have been reported in the literature, and those confirmed by histopathology are even fewer.11, 12, 13, 14, 15 Also, there are some autopsy reports of HSCT recipients who had evidence of CNS GVHD.16, 17 Finally, there are experimental reports of GVHD in animals, suggesting that the CNS is not immune to GVHD and that it is a potential target for alloreactive T‐cell/CD8+ lymphocytes.18, 19

Patients with CNS cGVHD may develop cognitive or focal neurologic deficits months to years after an HSCT, often after a reduction in their immunosuppression medication.6, 9, 10 Diagnosis is challenging, because there are many possible confounding factors, including infections, drug toxicity, autoimmune manifestations, and lymphoproliferative relapses, which can mimic the neurologic manifestations. A diagnosis of cGVHD involving the CNS should be entertained only after exclusion of the multiple other potential causes for CNS symptoms in these complex patients.6, 9, 10 It is important to exclude opportunistic infections through CSF testing, MRI, and sometimes even brain biopsy.6

The MRI may reveal white matter multiple sclerosis‐like lesions that are hyperintense in T2‐weighted and FLAIR sequences and can be contrast enhanced,8, 9 illustrating a possible disruption in the blood–brain barrier. CSF analysis can be normal but may show increased protein levels, oligoclonal bands, and variable pleiocytosis.6

In the histopathology findings, there is a morphologic similarity between infiltrates in the CNS and those observed in other organs.12 There is usually extensive perivascular and intraparenchymal lymphocytic and histiocytic inflammation. Immunohistochemistry can reveal a predominant T‐cell/CD8+ lymphocyte infiltrate, as reported in our patient. Two distinct histologic patterns of brain involvement can be observed: vasculitis presenting with CNS angiitis or microglial activation.11 The stereotactic biopsy was obtained from the right occipital lesion, as mentioned above; and, although it is likely that the pathology in the left globus pallidus and subthalamic nucleus was similar to the findings obtained in this biopsy site, it cannot be stated with any degree of absolute certainty. cGVHD can be treated with immunosuppressants (using combination treatments, consisting of 2 or 3 agents, including steroids) along with appropriate supportive therapy.6, 9

Conclusion

CNS cGVHD should be considered as a differential diagnosis for post‐HSCT patients who present with an inflammatory CNS disease and a movement disorder. In such complex cases, a diagnosis of cGVHD involving the CNS should be entertained only after exclusion of multiple other potential causes of CNS symptoms.

Author Roles

Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript preparation: A. Writing the First Draft, B. Review and Critique.

A. E.: 1A, 1B, 1C, 3A.

M. S.: 1A, 1B, 1C, 3A.

F. J. J.: 3B.

L. A. E.: 3B.

A. M. G.: 3B.

L. X. R.: 3B.

A. J. L.: 3B.

J. L. O.: 1A, 1C, 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for the previous 12 months: The authors report no sources of funding and no conflicts of interest.

Supporting information

A video accompanying this article is available in the supporting information here.

Video S1. This video demonstrates the hemichoreic‐hemiballistic movements of the right limbs at presentation and 6 months after treatment. Segment 1: In the first week, involuntary movements of the patient's right arm and leg were present at rest and were hyperkinetic, irregular, and large in amplitude, involving the proximal and distal portion of the limbs. The movements were of greater severity in the upper limb and increased in severity when she performed certain actions or with some postures. The involuntary movements decreased after 6 months of immunosuppressive and symptomatic treatment. Segment 2: At the last clinical follow‐up, there was a reduction in choreic and ballistic movements; however, there was still a degree of hemichoreic movement on the affected side, especially when the patient performed certain activities, such as grabbing a cup.