summarizes the clinical findings of the 8 male patients. All but one presented with LCH by age 2 years. The adult male (patient 8) was originally diagnosed at age 1. Seven patients had a CNS-Risk craniofacial bone lesion and one patient (Pt.7) may have since he had chronic otitis. Patient 7 also had an extensive LCH scalp rash for many months before treatment was begun. Four patients had diabetes insipidus (DI) and 4 had growth hormone deficiency. All patients were treated with vinblastine and prednisone and often 6MP for their primary LCH lesions. The CNS symptoms began an average of 5.8 years (range1.5–11 years) after the first evidence of LCH elsewhere in 7 patients. Patient 8 was not examined for an 8 year span, thus making it impossible to judge the true onset of his symptoms. Brain MRI scans showed T2-hyperintense signals in combinations of the cerebellar white and grey matter (8 patients), pons (7) basal ganglia (3), and medulla (1). Four patients had abnormalities of the hypothalamic/pituitary region including thickening of the pituitary stalk and loss of the posterior pituitary bright spot on sagittal T1-W images. Two patients (1,7) developed hydrocephalus as judged by increases in their ventricular dimensions on MRI scans before or near the time of onset of ND-CNS-LCH radiographic signs and the other 2 patients (3,8) 2–4 years after the CNS symptoms began. Patient 1 had mass lesions of the choroid plexus. Seven of 8 patients had ataxia, 4 dysarthria, 3 dysmetria, 2 dysphagia, and 1 developmental delay. Neurologic assessment using the Ataxia Rating Scale (ARS) was done in 7 patients. Disability points at the time of first assessment ranged from 19 to 28. Patients 1 and 2 developed petit mal seizure disorders 2–4 years after completing their vincristine/ARA-C treatment.
Patient Characteristics and Therapy for Primary LCH Lesions Prior to ARA-C Regimen
details the time on vincristine/ARA-C or ARA-C protocol and objective responses in ataxia rating scale and MRI images. Four of 8 patients (1,2,6,8) had improvements in their ARS scores within 2–6 months (). Patients 1 and 2 have had stable scores over follow-up periods of 7–3 years respectively. Patients 6 and 8 had initial improvements of the ARS scores, but subsequent worsening (increases pf 2 points) (). Patient 1 was treated with vincristine/ARA-C for 19 months because of slow response of his choroid plexus lesions, but his ND-CNS-LCH improved by the second month. illustrates the improvement in his handwriting after 2 months of treatment. His ataxia rating scores improved from 19 to 8 by the end of treatment. The score is now 1 at seven years from the end of vincristine/ARA-C treatment and had no other treatments after that regimen. Patient 2 also had improvement in the clarity of his speech with treatment until the 4th
month when his BAER had prolongation of latencies and his speech and ataxia worsened. It was thought that this could be evidence of vincristine toxicity so that drug was eliminated. After 4 more courses of ARA-C alone the BAER improved as well as his ataxia and dysarthria with ataxia rating scale points decreasing from 21 to 12. Patient 3 had an initial subjective response to vincristine/Ara-C, but then had marked peripheral neuropathy and weakness. In retrospect his mother remembered that he had similar problems during treatments with vinblastine. Thus, it was assumed that his deterioration was in part from vincristine neurotoxicity and this regimen was stopped. Although he seemed to have an initial good response to IVIG treatments every three weeks, he began a progressive decline in neurologic abilities. Treatment with tacrolimus seemed ineffective and made him excessively tired. At the time of stopping tacrolimus a review of serial MRI studies showed progressive hydrocephalus over the prior 3–4 years. A ventriculo-peritoneal shunt was placed followed by steady improvement in his strength, speech, and stamina. He now has further deterioration of strength and intellectual decline. Patient 4 presented with only dysarthia that improved quickly during ARA-C treatment and remains stable. Patient 5 presented with more than an 8 year history of ataxia, learning difficulty, and difficulty swallowing. He did not respond to ARA-C and is currently taking tacrolimus. Patient 6 had improvement in his ataxia, as judged by decrease in the ARS scores from 21 to 16, and behavior problems and has a stable response after 24 months. Patient 7 has previously been reported by Kereshenovich et al regarding his obstructive hydrocephalus. [ 9
] He developed an abnormal gait and decreased cognitive skills at age 8. MRI findings of CNS LCH began appearing at age 9.75 years and hydrocephalus at age 10.5 years. The patient had two endoscopic third ventriulostomies that were unsuccessful. A ventriculoperitoneal shunt was placed at age 10.6 years. His tremors and ataxia worsened after the shunt was placed, despite proper shunt function, and he was referred to our hospital for treatment recommendations. He had some improvement in his neurologic exam by the third month of treatment with ARS score improving from 25 to 19 (). However he then had progressive worsening (ARS score increased to 33) and has been given pulses of decadron with the ARA-C which improved his balance. It is difficult to judge when patient 8 began having ND-CNS-LCH signs or symptoms because he had no follow-up after age 8 years when he received the second course of RT for a mastoid lesion. In the following 17 years he had learning disability, bipolar disorder, substance abuse and finally hemiballism. At age 24, he was found to have non-communicating hydrocephalus of unknown etiology and a vetriculo-peritoneal shunt was placed. After 6 months of ARA-C his hemiballism disappeared and ataxia improved.
Handwriting samples of Patient 1. A. Before treatment with vincristine/cytosine arabinoside. B: After 2 months of treatment.
MRI scans of 5 patients (1,2,3,5,8) showed improvements at some time during their treatment.(–). Patients 3 and 5 had transient improvements in their clinical status that coincided with the improved MRI findings. However, both patients subsequently had clinical and radiologic deterioration. Patients 6 and 7 had no or minimal MRI changes. The MRI improvements consisted of relative decreases in the signal intensity in the cerebellum, pons, basal ganglia, or medulla. In no case did the abnormalities completely resolve.
BAER examinations were done on three patients (2,4,6). Patient 2 had a normal BAER in April 2003 just two months after radiologic evidence of ND-CNS-LCH (hyperintensity in the cerebellum, pons, midbrain and medulla), but no clinical signs were found. At age 6 6/12 there was increased latency of waves I and III which was worse 5 months later (age 6 11/12). The wave latency was stable when examined at age 7 3/12. After three months of vcr/ARA-C the latencies were worse and we decided to stop using vincristine. By age 7 10/12 (2 months after stopping ARA-C) the latencies had improved. Patient 4 had a single BAER examination one month before starting ARA-C that showed mild prolongation of wave form latencies. Patient 6 had severely abnormal brainstem central conduction of wave forms that was at the mid point of treatment, but worsened by the end of treatment. His ARS score improved from 21 to 16. The only toxicities besides neuropathy in patients receiving vincristine were grade 1–2 neutropenia and mild elevation of liver enzymes.