CSF pleocytosis in the setting of varicella zoster reactivation
Clinical Summary
Patient is a 15-year-old African American male with a history of T-cell ALL, now in remission. Around 2-3 weeks after completing first cycle of nelarabine treatment, he presented with subacute and progressive weakness involving both legs initially, followed by later involvement of both arms. Clinical exam showed distal greater than proximal weakness, with involvement of legs more than arms. Position and vibration sense deficits were also notable. While his weakness appeared to have plateaued, his spine MR imaging continued to show evolving changes with expanding T2 hyperintensities in posterior and central regions along the entire length of the cord. EMG/NCS showed axonal type sensori-motor polyneuropathy which progressed in severity when the study was repeated 1-2 months later. Complicating his presentation was the emergence of shingles in the trigerminal distribution. With varicella zoster reactivation, CSF showed elevation of WBC and protein, together with a positive varicella PCR for 6,600 copies. There was no evidence of CSF blast cells. Metabolic work up was negative.
Differential Diagnosis
The important differential diagnoses to consider consider here are the following:
Chemotherapy induced neurotoxicity in the form of subacutely evolving neuropathy and myelopathy: The correlation of symptom onset following nelarabine treatment, tempo of clinical progression, and selective involvement of posterior and central columns of the spinal cord all support a toxic, neurodegenerative pathology.
Varicella myelitis with preexisting peripheral neuropathy: Patient was immunocompromised and showed inflammatory changes in his CSF, together with clinical, and PCR evidence of varicella zoster infection. However, CSF pleocytosis and positive PCR evidence of varicella zoster DNA can be present in uncomplicated cases of varicella reactivation — even in immunocompetent subjects.[13] The absence of additional significant cognitive and myelopathic symptoms (following varicella reactivation) lowered the suspicion for superimposed varicella encephalomyelitis.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) — Concurrent illness variants (i.e., from T-cell ALL): The pattern of progressive motor/sensory deficits (symmetric, with distal and proximal involvement) as well as diffuse hyporeflexia in this case can be suggestive of this diagnosis. However, the absence of both demyelinating feature on the nerve conduction studies and albumin-cytologic dissociation on the CSF profile evidence against this impression. Also, concurrent illness variants of CIDP are more likely to occur with lymphomas, rather than leukemias as in this case.
Metastatic disease with leukemic infiltration to the cauda equina: Though the CSF was at one point positive for blast cells, post-remission CSF did not show any cell atypia. Furthermore, the MRI did not show meningeal enhancement or nodularity to support nerve root involvement.
Discussion
CNS Toxicity of Nelarabine
Nelaramine neurotoxicity should be strongly considered here as the patient had exposure to the drug in question, evidence of dorsal column involvement, as well as electrodiagnostic evidence of sensori-motor polyneuropathy (axonopathy). The sequential worsening of the MRI findings despite clinical stabilization suggests persisting and evolutionary progression of the initial pathophysiologic insult. The longitudinal involvement of specific tracts in the spinal cord is more suggestive of the neuronal degeneration and death in wallerian fashion rather than infectious etiology (which would probably be more widespread, especially in an immunocompromised patient). Such a slow and progressive change also supports the prolonged, long lasting effects of drug neurotoxicity.
Nelarabine is a second line drug approved by FDA for use as for the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma that has failed at least two chemotherapy regimens.[1,2] However it is known to have dose-limiting toxicities affecting central and peripheral nervous system. Symptoms of central neurotoxicity include somnolence, seizures, dizziness, confusion, and ataxia. Symptoms of peripheral neurotoxicity include paresthesias, pain in the extremities, and peripheral neuropathy. Furthermore, Guillian-Barre type of ascending paralysis, hypoesthesia, coma, status epilepticus, and craniospinal demyelination have described. Risk of neurotoxicity is increases with concurrent or previous intrathecal chemotherapy or craniospinal irradiation.
Pathogenesis
Nelarabine neurotoxicity has been postulated to be due to extremely high intracellular accumulation of Ara-G and its subsequent phosphorilation to Ara-GTP in neurons. It has been shown that brain and nerve tissue express high levels of deoxyguanosine kinase which converts Ara-G into Ara-GTP. Ara-GTP competes with deoxy GTP to be incorporated into DNA, thereby leading to DNA fragmentation and cell death.[3] The same process also leads to disruption in RNA synthesis and signal transmission.
Pathogenesis of Dorsal Column Degeneration
The association of dorsal column involvement with nelarabine toxicity has not been formally reported and thus the underlying pathogenic mechanism is less certain. For this patient, his vitamin B12, homocysteine, methylmalonic acid levels have all been normal although these serum levels can be unreliable indicator of the true metabolic status in leukemic patients. It has been postulated that neurotoxic agents can either directly or indirectly alter the metabolic milieu in the nervous system and lead to metabolic insult similar to the effects of vitamin B12 deficiency on the dorsal column tracts (with features of both axonal loss and demyelination).
Proposed pathogenesis of dorsal column degeneration:
Cytotoxic nitric oxide (NO) is formed, arising from a range of inflammatory, neurotoxic, and ischemic pathologies.
NO reversibly inhibits mitochondrial respiration by competing with cytochrome oxidase for oxygen, thus contributing to cytoxicity.
At sites of inflammation, axons exhibit early wallerian degeneration if they are conducting impulses at physiological frequencies while exposed to NO.[10] This was experimentally proved in rat dorsal roots where formation of myelin ovoids and frank axonolysis occurred in more than 95% of fibers when concurrently exposed to NO and sustained impulse activity.
Cobalamine species participate in redox reactions [11,12] with NO under aerobic conditions, thereby inactivating its physiological roles. In turn, NO oxidizes the cobalt core of vitamin B-12 from a 1+ to 3+ valance state, rendering methylcobalamin inactive.
Inactivated methylcobalamine inhibits homocysteine conversion to methionine and thereby deplete the supply of S-Adenosyl methionine (SAM). SAM deficiency results in abnormal methylation of phospholipids such as phosphatidylcholine, and is linked to central myelin defects and abnormal neuronal conduction. This is metabolic basis for dorsal column degeneration.
These disturbances of local cobalamine and folate metabolism and the resulting depletion/inactivation of the required cofactors can occur despite "normal" serum vitamin B12, folate, homocysteine, and methylmalonic acid levels.
High dose vitamin B12 supplements, to support the methyl-tetrahydrofolate pathways during chemotherapy may be helpful.
Varicella Myelitis
Varicella myelitis usually emerges in the setting of varicella zoster reactivation. It can also arise as a post-infectious syndrome and has been known to be associated with longitudinally extensive transverse myelitis in patients with aquaporin antibodies.[4] Varicella myelitis is thought to occur in 0.3 % [5] of varicella zoster infections, but can be as high as 25% in immunocompromised hosts.[6] It is not always preceeded by the dermatomal rash [7] and presents with motor or sensory involvements that can be bilateral or unilateral below the level of lesion. Symptoms can emerge within few days to weeks after rash (if present). Sphincter involvement is common. Sensory involvement is typically more of spinothalmic tract than the posterior column deficits.[8] In immunosuppressed patients, varicella myelitis can be much more fulminant with necrotic vasculitic involvement, and can manifest without a dermatomal rash.[9]
Diagnosis is established by supportive clinical picture (evolving myelopathic signs/symptoms), laboratory data (CSF pleocytosis, increased protein concentration, intrathecal anti-varicella zoster antibodies, and positive PCR evidence of varicella zoster DNA), and cord imaging (focal hyperintensities, diffuse edema, with variable enhancement ranging from mild patchy to more diffuse involvement including the meninges). However, it is important to establish objective and evolving myelopathic features for this diagnosis, since subclinical extension of viral inflammation into the CNS (including abnormal CSF and MRI findings) can occur commonly in uncomplicated cases of varicella zoster reactivation.[13] These uncomplicated cases consist of immunocompetent subjects without clinical signs of meningeal irritation, encephalitis, or myelitis. The absence of additional significant myelopathic symptoms (following varicella reactivation) lowered the suspicion for superimposed varicella myelitis in this case. Also, spinothalmic tracts are usually more involvement than the posterior column in varicella myelitis.[8] Isolated dorsal column involvement in zoster myelitis has not been formally reported. All of these features evidence against varicella myelitis as an independent, primary pathogenic process in this patient.
Clinical Course and Follow-up
The patient responded to antiviral treatment with acyclovir and clinically stabilized with physical/occupational therapy to maintain minimal ambulation with walker. Follow up MRI showed progression although his CSF PCR showed reducing varicella DNA copies. He underwent haploidentical peripheral blood stem cell transplantation (PBSCT) and then bone marrow transplant but later developed graft versus host disease and chronic renal insufficiency. He had recurrent bacterial, viral and fungal infections including candidiasis, aspergillosis, HHV6 infections. He showed clinical manifestations of liver and splenic abscesses, diffuse pneumonia, fungal sinusitis, fibrinous pericarditis, and succumbed to his disease with multiorgan failure. His autopsy report reflected his medical condition and his spinal cord showed dorsal column degeneration.
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