Clinical Case of the Month – Neurological presentation of TA-TMA: beyond the central nervous system

Title: Rare Peripheral Nervous System Involvement in Transplant-Associated Thrombotic Microangiopathy: A Diagnostic Challenge.

Submitted by: Rachele De Domenico, Hematology resident at University of Brescia and ASST Spedali Civili di Brescia, Italy, Hematology resident at University of Brescia, currently fellow at Institut Català d'Oncologia, Barcelona, Spain.

Physician expert perspective: Alberto Mussetti, Director Hematopoietic Cell Transplant/Cell Therapy Unit - Institut Català d’Oncologia - Campus Salut Bellvitge Comprehensive Cancer Center, Barcelona, Spain.

Clinical Case Summary

In March 2025, a 43-year-old woman with no relevant past medical history presented with severe pancytopenia and was subsequently diagnosed with high-risk myelodysplasia-related acute myeloid leukemia (MR-AML, WHO 2022). 

Following first-line treatment failure with standard 7+3 induction, she received three cycles of azacitidine plus venetoclax, achieving a morphological complete remission (CR) with persistent minimal residual disease (MRD). In October 2025, the patient experienced disease progression and underwent salvage chemotherapy with one cycle of FLA-IDA, re-inducing morphological CR with persistent MRD positivity.

Finally, in January 2026, the patient underwent allogeneic hematopoietic cell transplantation (allo-HCT) from a fully HLA-matched unrelated donor (12/12) after myeloablative conditioning with thiotepa, busulfan, and fludarabine. Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant cyclophosphamide (PTCy), mycophenolate mofetil, and tacrolimus.

Bone marrow evaluations performed at +1, +2, and +3 months post transplantation showed morphological CR, negative MRD, and 100% full donor chimerism.

The early post-transplant course was characterized by multiple severe complications, including BK virus-associated hemorrhagic cystitis, CMV colitis and and stage 2 skin and stage 2 gastrointestinal acute graft-versus-host disease (aGVHD; overall MAGIC grade III), the latter requiring high-dose corticosteroid therapy (methylprednisolone 2 mg/kg), with subsequent complete clinical resolution.

In March 2026, the patient was admitted for severe dorsolumbar pain, progressive lower-extremity weakness resulting in functional impotence, and sphincter dysfunction. 

Brain and whole spine MRI were unremarkable. Lumbar puncture showed mild proteinorrachia without pleocytosis and negative viral PCR panels. Electromyogram excluded acute neuronal damage. 

Concomitant laboratory tests showed new on set thrombocytopenia, elevated lactate dehydrogenase (LDH) levels, consumed haptoglobin, schistocytes on peripheral blood smear and a normal coagulation profile, supporting the diagnosis of high-risk transplant-associated thrombotic microangiopathy (TA-TMA) according to harmonized consensus criteria, due to concurrent CMV colitis. Tacrolimus was promptly discontinued and later switched to sirolimus, and therapeutic plasma exchange was initiated.

The neurological manifestations progressively improved without specific target treatment and as plasma exchange therapy progressed with normalization of the TA-TMA laboratory markers and immunosuppressive adjustment. The patient was discharged without residual neurological impairment.

Question

Based on the clinical presentation and laboratory findings, which of the following represents the most likely cause of the patient's neurological manifestations?

1. Cytomegalovirus (CMV) radiculoplexopathy
2. Guillain-Barré syndrome
3. Peripheral nervous system involvement secondary to Transplant-Associated Thrombotic Microangiopathy (TA-TMA)
4. Tacrolimus-induced Posterior Reversible Encephalopathy Syndrome (PRES)
5. Steroid-induced Critical Illness Myopathy (CIM)

Expert Perspective

Neurological complications following hematopoietic cell transplantation (HCT) are common and often represent a major diagnostic and therapeutic challenge due to a broad spectrum of etiologies. These include neurotoxic drugs (i.e calcineurin inhibitors [CNIs], cytotoxic agents such as methotrexate, busulfan or fludarabine etc.), infectious pathogens (viruses, bacteria, fungi and parasites), cerebrovascular illness, metabolic encephalopathies, immune-mediated phenomena including neuro-GvHD. Additionally, central nervous system (CNS) relapse of the underlying disease, transplant-associated thrombotic microangiopathy (TA-TMA), and post-transplant lymphoproliferative disorder (PTLD) must be carefully ruled out. Given that clinical presentations are often atypical and nonspecific, establishing the correct etiology frequently proves to be a prolonged and complex process [1 - 3].

TA-TMA is a severe, life-threatening post-transplant complication driven by endothelial injury, microvascular thrombosis, and dysregulated complement activation [4-7.  Systemic endothelial damage is triggered by conditioning regimens, CNIs, GVHD and viral reactivations (such as CMV or BK virus) [6, 8].

Unlike other thrombotic microangiopathies such as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), TA-TMA is typically characterized by normal ADAMTS-13 activity and an unaltered coagulation profile, reflecting a localized microvascular process driven primarily by endothelial and complement dysfunction rather than systemic clotting factor consumption [7, 9].

Diagnosis relies on consensus laboratory and clinical criteria, including persistent thrombocytopenia, microangiopathic hemolytic anemia (characterized by schistocytes on blood smear, elevated LDH and decreased haptoglobin) and progressive organ dysfunction [10, 11].Organ involvement in TA-TMA is multi-systemic, frequently compromising the kidneys, lungs, gastrointestinal tract, heart, and nervous system [4,10, 11].

Furthermore, validated criteria for high-risk TA-TMA—comprising proteinuric renal impairment, elevated soluble C5b-9, peak LDH exceeding twice the upper limit of normal, organ dysfunction beyond stage I acute kidney injury, concurrent grade II–IV acute GvHD, and active systemic infection—identify patients with a dismal prognosis who require immediate therapeutic intervention [10, 12].

Neurological manifestations of TA-TMA classically affect the central nervous system (CNS), presenting as confusion, altered mental status, focal deficits, seizures, or posterior reversible encephalopathy syndrome (PRES) [12-14].

Conversely, peripheral nervous system (PNS) involvement is rare. The pathophysiological mechanism involves severe endothelial and microvascular injury within the vasa nervorum, leading to localized microvascular ischemia of peripheral nerve trunks and nerve roots. Clinical presentations can mimic inflammatory or infectious polyradiculopathies, presenting with acute or subacute motor weakness, painful neuropathies, and sphincter dysfunction [15].

Differentiating PNS involvement of TA-TMA from other post-transplant neuromuscular complications—such as CMV-induced polyradiculopathy, Guillan-Barrè syndrome, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), or Critical Illness Myopathy/Neuropathy (CIM/CIN)—is particularly complex [15, 16]. Neuroimaging (brain and spinal cord MRI) in PNS TA-TMA is characteristically unremarkable, and cerebrospinal fluid (CSF) analysis typically fails to demonstrate cellular pleocytosis or viral pathogens [16]. Electromyography (EMG) often demonstrates non-specific, overlapping patterns consistent with critical illness myopathy, which can further obscure the primary vascular etiology [17]. Consequently, confirming PNS TA-TMA relies on establishing a strong temporal relationship between the onset of neurological deficits, systemic laboratory markers of active microangiopathy, and clinical improvement following TMA-targeted interventions [15, 18].

The therapeutic management of TA-TMA centers on the immediate withdrawal or replacement of potentially triggering calcineurin inhibitors [18]—typically transitioning to mTOR inhibitors such as sirolimus—alongside target-driven strategies including complement blockade (e.g., eculizumab, ravulizumab or narsoplimab) [19, 20]. Therapeutic plasma exchange may be utilized to remove circulating endothelial toxins, pro-inflammatory cytokines, and activated complement components. [11, 12, 18, 21].

In conclusion, post-allo-HCT neurological complications encompass a highly complex array of infectious, toxic, metabolic, and vascular etiologies [1 - 3]. As exemplified by this case, TA-TMA can manifest with rare and atypical neurological features, underscoring that clinicians ought to maintain a high index of suspicion and systematically include TA-TMA in the differential diagnosis of post-transplant neurological complications [15]. Ultimately, early recognition, prompt withdrawal of triggering agents, and timely initiation of TMA-directed therapies are crucial to achieving complete neurological recovery and preventing irreversible end-organ damage [10, 11, 18].

CORRECT ANSWER  –  C

While peripheral nervous system (PNS) involvement is rare in TA-TMA, microvascular endothelial damage and thrombosis can affect the vasa nervorum, leading to neuromuscular deficits. The strong temporal correlation between the resolution of neurological symptoms, normalization of TMA laboratory markers, calcineurin-inhibitor withdrawal and response to plasma exchange confirms TA-TMA as the primary etiology.

Incorrect (A): CMV polyradiculopathy was a strong clinical suspect given concurrent CMV colitis, but normal CSF analysis and negative CMV PCR make this diagnosis unlikely.

Incorrect (B): Guillain-Barré syndrome (GBS) can present with progressive ascending lower-limb weakness and sphincter involvement following viral reactivation or immune dysregulation; however, GBS does not account for the systemic microangiopathic hemolytic anemia or thrombocytopenia, and highly suggestive albuminocytologic dissociation in the cerebrospinal fluid was absent.

Incorrect (D): PRES typically presents with central nervous system signs (encephalopathy, seizures, visual disturbances, hypertension) and characteristic subcortical vasogenic edema on brain MRI, which was completely unremarkable in our case.

Incorrect (E): Although high-dose corticosteroid exposure for aGVHD can induce CIM (and EMG findings may overlap), a simple steroid myopathy would not cause acute sphincter dysfunction or respond rapidly to CNI withdrawal and plasma exchange.

References

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2. Schmidt-Hieber M, Velasco R, Penack O, et al. Central nervous system complications after allogeneic haematopoietic cell transplantation: best practice recommendations from the EBMT practice harmonisation and guidelines committee on epidemiology, outcome and neuroimaging. Bone Marrow Transplant. 2026;61(8):983-992. doi:10.1038/s41409-026-02869-2
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