J
Finsterer
Neurologisches
Krankenhaus Rosenhügel, Vienna, Austria, Europe
Corresponding
author:
Univ.Prof.
DDr. J. Finsterer
Email: fipaps@yahoo.de
SMJ 2008 53(2): 65
Abstract
Objectives:
Diagnosing mitochondrial disorder (MCD) is challenging if symptoms and signs of
a second trouble overlap with those of the MCD.
Case
report: A 54-yo male developed muscle pain in his proximal lower and distal
upper limbs, easy fatigability and exercise intolerance, and myoglobinurea.
Based upon the clinical presentation, recurrent creatine-kinase elevation,
highly abnormal lactate stress testing, abnormal muscle biopsy, and a positive
MRI spectroscopy, MCD was diagnosed. Based upon progressing pain of the lower
limbs, the development of claudication, recurrent falls, nightly, muscle
cramping, gait disturbance, erectile dysfunction, the inability to sit, and an
angiography revealing stenosis of the distal aorta, occlusion of the right iliac
and left internal iliac and stenosis of the left external iliac artery, Leriche-syndrome
was diagnosed. He profited from stenting of the left external iliac artery.
Manifestations of MCD remained stable throughout the period of observation.
Conclusion:
If the history is misleading or if manifestations of a MCD overlap with those of
a Leriche-syndrome, diagnosing either condition is challenging, Atherosclerosis
may be a feature of mitochondrial disease
Key
words
respiratory
chain, oxidative phosphorylation, encephalomyopathy, mitochondriopathy,
mitochondrial cytopathy, cerebrum, brain, spinal cord, multi-system disease
Introduction
Diagnosing
mitochondrial disorders (MCDs) is a challenge, particularly if the diagnostic
facilities and financial resources are limited [1,2]. Diagnosing MCDs is even
more challenging if symptoms of a concomitant second trouble overlap with those
of the MCD. If no ultrastructural, biochemical, or genetic investigations are
feasible, the diagnosis of MCDs relies on the history, clinical examination,
blood chemical investigations, stress tests, cerebrospinal fluid investigations,
nerve conduction studies, electromyography, and light microscopy and
immunehistology of the skeletal muscle [3]. If one of these puzzle stones is not
reliable or in case of a second trouble, mimicking MCD, diagnosing MCDs is
perturbed.
Case
report
The patient is a 54-yo Caucasian male with a history of a Brody abscess in the head of the right tibia in 1974, a car accident with a polytrauma in 1982, and transient weakness for extension of the right foot during two weeks in 1984. His family history revealed death from stroke of his mother and father but was otherwise uninformative, particularly for neuromuscular disorders. The patient was a passionate cyclist, riding 60-80km/d, but he also smoked 30 cigarettes per day since 30y. No other cardiovascular risk factors were present. He reported an increase of 8kg since spring 1998 because of reduced mobility. In June 1998 he experienced acute aching of both thighs during cycling for the first time, which prompted him to rest for 10 minutes to continue without problems thereafter. Since then he also noted generalized fatigue and an increased desire to sleep. Since June 1998 the distance after which he experienced muscle pain in both thighs contiguously decreased such that in September 1998 muscle aching occurred already after a distance of 1 km of walking. He also reported spontaneous and persisting muscle pain, muscle cramps, and aching in both lower arms since August 1998, being similar to those of the lower limbs and being enhanced by exercise. He also mentioned one episode of myoglobinuria (table 1). He was regularly taking magnesium for muscle cramping and vitamin B.
Table 1. Mamifestations of MCD and Leriche-syndrome
in the describer patient
MCD
Leriche-syndrome
General fatigue x no
Increased sleep desire
x
no
Easy fatigability
x
no
Muscle pain of upper and lower limbs
x
no
Erectile dysfimction
x
x
Myoglobinurea
x
no
Claudication
x
x
Nightly muscle cramps
x
x
Falls
x
x
Recurrent creatine-kinase elevation
x
no
Abnormal lactate stress test
x
no
Ragged-red-like muscle fibres
x
no
Subsarcolemmal accumulation of OE
x
no
Abnormal MR spectroscopy
x
no
Abnormal MR angiography
no
x
OE: oxidative enzymes, x: indicative of the disorder
Clinical
neurologic examination in September 1998 was normal. Arterial pulses on the
limbs were palpable. Body-weight was 78kg. Blood-work revealed a cholesterol of
236mg/dl (n: <200mg/dl) and a creatine-kinase of 85U/l (n: <70U/l). A CT scan of the cerebrum was normal, in particular there was no
lacunas, leucaraiosis, or calcified or stenosed carotid or basilary arteries. A
CT scan of the thorax was normal, without evidence for calcification of the
aorta or the coronary arteries. Nerve-conduction-studies of the right sural
nerve showed slightly reduced nerve conduction velocity. Needle electromyography
of the right rectus femoris muscle was equivocal.
At follow-up in October 1998 clinical neurologic examination again was normal. The circumference of the thighs was 48.5cm on the right and 49.5cm on the left side. Blood-work showed normal creatine-kinase and normal resting lactate. Lactate-stress-testing, according to an established protocol [4], however, was highly abnormal with a maximal increase of serum lactate to 4.5mmol/l (n: <2.1mmol/l) after 10 minutes of cycling with 30W on a bicycle ergometer (figure 1). Needle electromyography of the right rectus femoris muscle was non-informative. Muscle biopsy of the right lateral vastus muscle in November 1998 revealed slight fiber-size variability, internalized myonuclei, ragged-red-like muscle fibers, and subsarcolemmal accentuation of the oxidative enzymes. PAS-staining was normal and thus myophosphorylase deficiency excluded. Possible MCD was diagnosed. In February 1999 he reported hypesthesia of the digits 4 and 5 of the right foot. His body weight had increased to 82kg. Vitamin C and L-carnitine were prescribed but withdrawn by the patient shortly after initiation. In May 1999 deterioration of gait by 70% compared to September 1998, extension of the muscle cramps towards both lower legs, and easy fatigability after slight exercise were reported. Clinical neurologic examination was unchanged. Myasthenia gravis was excluded upon normal low-frequency repetitive nerve stimulation.
The
further course until December 2001 was only poorly documented. Since June 1999
the patient complained about recurrent falls, severe pain of the pelvic girdle
and the lower limbs and inability to carry even 1kg or a coffee cup with his
hands. He reported pain of his buttocks already after a few minutes of sitting.
A MRI spectroscopy in September 2000 revealed a relative increase of mono- and
diesters, compatible with a metabolic myopathy. In December 2001 a vascular
disorder of the lower limb arteries was suspected. In January 2002 MR-angiography
and conventional angiography of the aorta and the pelvic arteries revealed
stenosis of the distal aorta, occlusion of the right pelvic arteries, the left
internal iliac artery, and a high-grade stenosis of the left iliac artery. The
common femoral. superficial femoral, and anterior tibial arteries, were normal
bilaterally. The posterior tibial arteries were narrow in diameter. Peripheral
arterial occlusive disease IIb of the distal aorta and the iliac arteries (Leriche-syndrome)
with a walking distance of 15m before pain occurred was diagnosed. In January
2002 the patient underwent percutaneous transluminal angioplasty, during which a
stent was implanted into the left external iliac artery. At that time he was
smoking 10 cigarettes per day and his body weight was 76kg. Immediately after
angioplasty he reported a sudden 90% reduction of his complaints, respectively
an almost complete recovery. He could walk again 10km without complaints. After
angioplasty the patient additionally developed hypothyroidism after struma
resection, osteoporosis, and hyperlipidemia. In January 2006 he was taking
acetyl-salicylic acid (100mg/d), vitamin D, calcium and levo-thyroxin
(0,16mg/d).
Discussion
The
described patient was obviously affected by two different disorders, which both
presented with overlapping manifestations, why the diagnosis of both disorders
was perturbed. On the one hand there were indications for a MCD, affecting the
muscle. On the other hand there was occlusive atherthrombotic disease of the
distal abdominal aorta and the iliac arteries. Differential diagnoses initially
considered were a tandem vertebrostenosis, polyradiculitis, syringomyelia,
arterio-venous fistula, disc prolapses, malignancy including lymphoma, and
osteoporosis [5]. After excluding these differentials upon the presented
findings, a metabolic myopathy was assumed. Arguments for a metabolic myopathy
were the general fatigue, easy fatigability upon slight exercise, increased
sleep desire, declining physical fitness, muscle aching in the upper and lower
limbs (tetrasymptomatology), spontaneously and after exercise, erectile
dysfunction, recurrent creatine-kinase elevation, an episode of myoglobinurea, a
prominently abnormal lactate stress test, the muscle biopsy findings with
ragged-red-like muscle fibers and slight irregularities of the oxidative
enzymes, and the abnormal MR-spectroscopy [7]. Whether thyroid dysfunction,
hypercholesterolemia, and osteoporosis, frequently associated with MCDs, were
further manifestations of a systemic metabolic defect, remains speculative.
Though there is little evidence from the literature it cannot be definitively
excluded that even arterial occlusive disease was a manifestation of the MCD.
Unfortunately, it was not feasible to conduct a biochemical work-up of the
muscle biopsy, polarography, or genetic studies to support the assumption of a
generalized metabolic defect, particularly of the oxidative metabolism.
Clinical
manifestations attributable to occlusive vascular disease included
exercise-induced muscle pain in the thighs, nightly cramping starting >1 year after onset his complaints, erectile dysfunction, and repeated
falls. Within one year after onset the clinical picture and the instrumental
findings were not indicative of iliac artery atherosclerosis given the extensive
sport activity, the absence of a history of angina pectoris, myocardial
infarction, stroke, or vertigo, similar muscle pain in the thighs and lower arms
(tetrasymptomatology), absence of risk factors for atherothrombotic disease,
like diabetes, arterial hypertension, or severe hyperlipidemia, the occurrence
of claudication not earlier than after a walking distance of 1 km, normal pulses
on the lower limbs, and the absence of vascular disease on cerebral and thoracic
CT scans. Pulses on the lower limbs, however, may be palpable even if the
proximal arteries are completely occluded and sufficient collaterals have
developed to compensate for the deficient vascular supply. The cause of
occlusive vascular disease in the described patient remains speculative. The
only risk factor was the long-standing nicotine abuse. Assuming nicotine as
causative, however, one would expect a much more widespread distribution of
atherosclerosis and not a strict focal manifestation [8]. Why such a severe,
focal manifestation developed despite the presence of solely a single risk
factor and excessive physical activity favors additional factors to have
contributed to the development of the vascular disease.
Diagnosis
of occlusive vascular disease in the described patient was possibly delayed
because of the overlapping complaints attributable to MCD or Leriche-syndrome
(table 1), the MR spectroscopy, indicative of a metabolic defect, and the
patient’s misleading and confusing statements. He reported weakness of the
upper limbs and muscle pain and muscle cramps in the upper and lower limbs,
which is by far not indicative of Leriche-syndrome. He reported general fatigue,
increased sleep desire, and easy fatigability upon slight exercise, symptoms
also incompatible with a focal problem of the lower limbs. Not earlier than one
year after onset of his complaints he reported reduced erectile dysfunction,
nightly pain, gait disturbance, and recurrent falls, although clinical
neurologic examination was repeatedly normal. He also reported a 70%
deterioration of gait between September 1998 and May 1999 (11 months), but did
not mention further progress until January 2002 (32 months). Given the initially
progressing nature of his complaints he should have had the need to reinforce
the diagnostic work-up, particularly after May 1999. Additionally, severity and
progression of complaints was poorly documented between June 1999 and January
2002. Because of the patient’s misleading complaints a local vascular problem
of the lower limbs was not within the scope of differentials and was suspected
not earlier than 3.5y after onset. Further inconsistencies of the patients
history additionally hampered the credibility of his statements. It is unlikely
that stenting of the left external iliac artery resulted in an immediate 90%
improvement of his complaints. This would imply that the right leg was supplied
by the stenosed left external iliac artery. Since no collaterals from the left
external iliac artery to the right common femoral artery were seen on MR-angiography
and since no pulses were palpable on the right lower leg after the intervention,
such a scenario is rather unlikely. It is also unlikely that a stented stenosis
showed no dynamics, particularly since he did not give up smoking and had
developed hypercholesterolemia [9,10].
This
case shows, that diagnosing MCD clinically overlapping with Leriche-syndrome
remains a challenge, Diagnosing definite MCD in the presence of a second trouble
requires a reliable history and sophisticated methods. For optimal treatment of
occlusive vascular disease early recognition is desirable.
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