Figure 1. First irradiation field Figure 2. Second irradiation field,
re-irradiation
Cancer Therapy Vol 2, 423-428, 2004
Case report on combined radiation myelopathy and intramedullary
metastases
Robbert JHA Tersteeg1, Sherif Y El Sharouni1*, Henk B Kal1, Gerard
H Jansen2, Petra M De Jong
3, Jacobus S. Straver 4
1Department of Radiation Oncology, University Medical
Center, Utrecht, The Netherlands
2Department of Pathology, University Medical Center,
Utrecht, The Netherlands
3Department of Pulmonology, Hofpoort Ziekenhuis,
Woerden, The Netherlands
4Department of Neurology, Hofpoort Ziekenhuis, Woerden,
The Netherlands
__________________________________________________________________________________
*Correspondence: SY El Sharouni, MD, University Medical Center Utrecht, Dept. of
Radiation Oncology, Q 00.118, Heidelberglaan 100, 3584 CX Utrecht, The
Netherlands; Fax +31 30 2581226; e-mail: S.Y.ElSharouni@azu.nl
Key words: radiation myelopathy, intramedullary metastases, MRI, neurological
complications
Abbreviations: biologically effective dose,
(BED); cerebral spinal fluid, (CSF); computerized tomography, (CT);
linear-quadratic, (LQ); Magnetic Resonance Imaging, (MRI)
Summary
Radiation
myelopathy is one of the complications most feared in radiotherapy. The
clinical picture consists of central motor neuron signs, sometimes without loss
of sensibility. Radiation myelopathy is preceded by a latency period, during
which the patient is asymptomatic. We present a patient with combined radiation
myelopathy and intramedullary metastases. Our patient was a female, aged 47,
who showed a large-cell squamous cell carcinoma of the lung. She received
palliative irradiation to the lung. Nine months later the patient experienced
paraesthesia in her left leg and difficulty in stair climbing especially with
her left leg. Within a few weeks these complaints extended to her right leg and
urine incontinence developed. MRI imaging of the thoracal spine showed
intramedullary metastases at vertebrae Th5 / Th6. She was reirradiated; the
irradiated part of the myelum was partially included in the prior treatment.
Two months after the last radiation treatment she developed complaints of
numbness of the right arm, without loss of strength. Further investigations confronted
us with combined radiation myelopathy and intramedullary metastases.
Radiation myelopathy is one of the complications most
feared in radiotherapy. It was first described by Ahlbom (1941). The clinical
picture consists of central motor neuron signs, sometimes without loss of
sensibility (Goldwein, 1987). Diagnosis can be difficult with a paraneoplastic
syndrome, herpes zoster or myelopathy as a result of chemotherapy and epidural
/ intramedullary of leptomeningeal metastases as differential diagnosis.
Radiation myelopathy is preceded by a latency period,
during which the patient is asymptomatic. Symptoms begin as paresthesia and/or
inability to perceive pain and/or temperature. In literature the latency period
has been reported to last from 1 month to 6 years. Typically, the median
latency is 6 months. About three out of four patients develop myelopathy within
18 months after radiation treatment (Goldwein, 1987; Michikawa et al, 1991;
Koehler et al, 1996).
Diagnosis is in fact a diagnosis per exclusionem. The
three criteria for myelopathy as a result of radiation treatment according to
Pallis et al, (1961) are:
1. the spinal cord must have been included in the
radiation field
2. the main neurological lesion must be within the
segments of cord exposed to radiation and
3. metastases or other primary spinal cord lesions must
be ruled out as the cause of the neurological disorder.
Recommended for further diagnostics are lumbar
puncture and myelography, as well as CT- (computerized tomography) and MRI-imaging
(Magnetic Resonance Imaging) (Goldwein, 1987). Analysis of the cerebral spinal
fluid (CSF) might reveal an elevated protein. The myelogram in some cases
demonstrates mild cord atrophy. Myelography is only advised in case of
contra-indications for MRI, because of the superior imaging quality of the latter.
CT/MRI imaging is also important to rule out the presence of intramedullary
tumour (Schiff and OÕNeill, 1996). Other causes of myelopathy could be excluded
by means of MRI.
Pathological changes of the myelum are described in a
number of studies. Both early and late changes can be distinguished
(Schultheiss et al, 1988; Van Daal et al, 1989; Van der Kogel, 1997).
A bimodal distribution of latencies has been described
(Goldwein, 1987) with peaks occurring at 13 months and 26 months after
irradiation. Patients with shorter intervals have, in general, been treated
with higher radiation doses. This supports the hypothesis of two mechanisms of
damage to the spinal cord: white matter necrosis at higher doses and vascular
damage at lower doses. Patients undergoing a reirradiation showed a shorter
latency period, as did paediatric patients.
Other causes of progressive myelitis must be excluded,
most notably extramedullary metastases, intramedullary tumour, necrotizing
carcinomatous myelopathy and hypertrophy of the posterior vertebral facets of
the laminae as a result of arthritis.
We present a patient with
combined radiation myelopathy and intramedullary metastases.
Our patient was a female, aged 47, without a medical
history. In August 1996 she developed complaints of pain in the right shoulder.
She also coughed, producing viscous sputum and there was some shortness of
breath while exercising. Finally, she developed fever and night sweat. At the
time of presentation she smoked two packs of cigarettes a day, no consumption
of alcohol. No abnormalities were found at physical examination.
A chest X-ray showed a large density in the upper
right lobe of the lung. A CT-scan of the thorax showed a large mass extending
into the mediastinum and a second mass ventrally, with probable destruction of
the rib, explaining the complaints of pain.
A bronchoscopy showed a tumour, just in front of the
ostium of the upper right lobe, causing a stricture to 60%, with submucosal
growth.
Pathological findings showed a large-cell squamous
cell carcinoma.
She received palliative irradiation to the lung, to a
dose of 39 Gy, in fractions of 3 Gy, administered by two opposing AP/PA fields.
The target area included the right upper lobe, the ipsilateral hilus and the
mediastinum. As a consequence the thoracic vertebrae Th 3 / Th9 were also included (Figure
1).
Nine months later the patient experienced paraesthesia
in her left leg and difficulty in stair climbing especially with her left leg.
Within a few weeks these complaints extended to her right leg and urine
incontinence developed. On neurological examination hyperreflexia of both legs
was found but at this time no sensory level at the trunk could be determined.
MRI imaging of the thoracal spine showed intramedullary metastases at vertebrae
Th5 / Th6. She was irradiated to a dose of 20 Gy in fractions of 4 Gy. The
target area was Th4 / Th7, irradiated in one PA field, the dose was given at a
depth of 6 cm. This was a reirradiation because the irradiated part of the
myelum was partially included in the prior treatment (Figure 2). Despite reirradiation the symptoms got worse resulting
in progressive paresis of both legs. Two months after the last radiation
treatment she developed complaints of numbness of the right arm, without loss
of strength.
Figure 1. First irradiation field Figure 2. Second irradiation field,
re-irradiation
Neurological investigation showed numbness in
dermatome C8 with hyper-abduction of the right arm but no pareses of the arms.
Loss of sensibility at the trunk (delineated at Th6 on both sides),
hyperreflexia of the legs and finally a Babinski reflex on both sides were
noted.
Imaging of the cervico-thoracical spine by means of
MRI showed abnormal signal in the myelum at C7 / Th5. In the cervical (not
irradiated) part of the spine, ring-like enhancing lesions were seen, arousing
suspicion of radiation myelopathy (Figure
3). In the thoracic (irradiated) part of the spine intramedullary metastases
were suspected (Figure 4).
The complaints were rapidly progressive; paresis in
the legs became complete. There was total urine incontinence.
Finally she died within three months after
reirradiation. Autopsy was performed.
The autopsy showed some surprising findings. In the
reirradiated area intramedullary metastases were found, histologically
corresponding with a squamous cell carcinoma (Figure 5). These metastases were found at the level of Th7. At the
levels C7 / Th1, corresponding with the neurological findings, changes were
seen, but not based on tumour. The found abnormalities mainly consisted of
vascular changes with subtotal necrosis and hyaline changes of the vessels (Figure 6). ). These findings match
radiation myelopathy.
Figure 3. MRI
cervical spine, showing suspected myelopathy Figure 4. MRI thoracal spine, showing
intramedullary metastases
Figure 5. Intramedullary
metastases of squamous
cell carcinoma in re-irradiated area
Figure 6. Vascular changes with
subtotal necrosis and hyaline changes of the vessels at level C7 / Th1.
Early changes in radiation myelopathy notably consist
of focal areas with spongious demyelination, axonal swelling and the absence of
observable vascular injury. Late changes are characterised by involvement of
the entire myelum with a preference for the white matter, as well as vascular injury
(Schultheiss et al, 1988; Ang and Stephens, 1994). Most studies report vascular
injury as the primary pathophysiological cause of radiation myelopathy. This
seems to be the explanation for the damage outside the irradiated volume as
seen with this patient. Vascular changes as a result of the formation of
hyaline membranes, necrosis and thrombosis can migrate into the course of a
blood vessel. In our case, however, we observed a short interval between the
second treatment and the complaints.
Recent MRI studies in Japan have mentioned a number of
characteristics that can almost be conclusive for myelopathy as a result of
radiotherapy: 1) swelling of the spinal cord on T1-weighted images and an
intramedullary high-intensity area on T2-weighted images (usually attributed to
spinal cord oedema, since the cord size diminishes following steroid
administration on subsequent MR images) and 2) a ring-like enhancing lesion
with gadolinium on T1-weigthed images, resulting from blood-brain barrier
breakdown (Michikawa 1991; Yasui 1992). In our case swelling of the spinal cord
as well as a ring-like enhancing lesion were indeed found. The three criteria
for myelopathy as a result of radiation treatment according to Pallis et al,
(1961) are:
A. The spinal cord must have been included in the
radiation field;
B. The main neurological lesion must be within the
segments of cord exposed to radiation;
C. Metastases or other primary spinal cord lesions must
be ruled out as the cause of the neurological disorder.
In our patient described, the spinal cord level of
neurological disturbances was located inside as well as outside the irradiated
area.
For every fractionation scheme a Biologically
Effective Dose (BED) can be calculated using the Linear-Quadratic (LQ) model
(Barendsen, 1982). The incidence of a biological effect according to the LQ
model is I = n (ad+bd2), and the BED that can be derived from
this linear-quadratic equation is nd(1+d/(a/b)); n is the number of fractions, d is the fraction
dose, and a/b
is a tissue parameter with values of about 10 Gy for acute reacting tissues and
a/b
is about 2 Gy for late reacting tissues.
A reasonable estimate of radiation myelopathy risk is
5% at 60 Gy in 30 fractions. This myelum tolerance dose results in a BEDtot
value of 60(1+2/2) = 120 Gy (with a/b is 2 Gy). The retreatment tolerance dose that can be
derived from reirradiated experimental animals and human patients is about 130%
of the BEDtot (Stewart, 1994). A prerequisite is that the interval
is at least 6 to 9 months and the first treatment dose has not exceeded about
65% of the BEDtot value. The total BED for reirradiation then is 156
Gy.
With our patient the first treatment BED1 =
39(1+(3/2)) = 97.5 Gy (this is 81% of the BEDtot). The BED2
of the second treatment is 5*4(1+(4/2) = 60 Gy. This sums up to 157.5 Gy. This
BED value of 157.5 Gy seems equivalent to the retreatment tolerance dose.
However, the dose of the first treatment delivered to the myelum was 81% of the
tolerance dose, and repair of induced damage was probably not complete between
the first and second treatment. Experimental data with animals show that the
tolerance dose after reirradiation is inversely proportional to the first dose.
For instance, after an initial dose of 50% of the BEDtot and a
sufficient time interval of at least 6 months, the retreatment tolerance dose
would be approximately 80% of the BEDtot, while after an initial
dose close to full tolerance (90% of the BEDtot), only a maximum of
40% of the BEDtot would be left for retreatment. Moreover there
probably remained substantial radiation-induced damage after the first (high)
dose in our patient. Thus the myelopathy observed in our patient could also
well be radiation induced.
The diagnostic pitfall in this case is the erroneous
assumption that the complaints of this patient can be attributed to the known
intramedullary metastases at Th7, which was confirmed by autopsy. However, this
level does not correspond with the eventual clinical findings, which point to a
localisation at the cervico-thoracal part of the myelum. These findings, as we
have shown by MRI and pathological investigations are most probably caused by
radiation myelopathy.
We recommend that in case of complaints after (re-)
irradiation, accurate imaging is performed, preferably by means of MRI with
gadolinium. One should always be aware of radiation myelopathy, even if the
level is not corresponding with the irradiated part of the myelum.
The retreatment dose of 20 Gy in 5 fractions of 4 Gy
could better have been reduced, with respect to the relatively high first dose
and short interval time, to 3 fractions, or to a scheme with a lower fraction
dose, e.g. 5x3 Gy. The BED of this alternative scheme is about 37 Gy,
significantly lower than the BED of 60 Gy.
One of the three criteria of myelopathy as result of
radiation according to Pallis et al: the main neurological lesion must be
within the segments of cord exposed to radiation, is not obligatory. This
criterion should be read as: Õthe main neurological lesion must be in or near
to the segments of the cord exposed to radiationÕ.
To date we have not found a resembling case in
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