Differential diagnosis of Herpes Zoster myelitis and ALS
Differential diagnosis of Herpes Zoster myelitis and ALSHerpes virus myelitis (HVM) develops in 1.2 – 6.3% of cases as a complication of herpes infection with a herpes-zoster virus (Varicella zoster) [1, 2]. This complication mainly occurs in immunodeficiency patients (HIV-infected persons with other causes for immunodeficiency after long-time treatment with steroids, diabetes mellitus, etc.).
Pathogenesis of HVM has been poorly studied so far. It is believed that a herpes-zoster virus activates in spinal ganglia due to immunodeficiency and can penetrate perineurally to the spinal cord parenchyma affecting the grey and white matter. The pathogenesis involves an allergic response, autoimmune vasculitis, demyelination, and virus invasion as such. In most cases, spinal cord pathologies occur after development of a vesicular rash, but neurological complications may appear with omitting this stage. The development of a rash several days or weeks before neurological symptoms appear allows the disease to be diagnosed etiologically.
The clinical pattern of HVM is presented by segmental and long-tract motor and sensory abnormalities, with predominating motor ones. Manifestation of sensory disorders and development of pelvic problems depend on the severity and duration of the affection (from no abnormalities in mild cases to severe disorders in transverse myelitis). Increased protein concentrations and reduction of glucose, lymphocytic pleocytosis are observed in the cerebrospinal fluid (CSF). Polymerase chain reaction (PCR) to Varicella zoster DNA in the CSF in HVM patients is rarely positive, however, positive reaction to this virus is commonly shown by blood PCR and serological reactions. The prognosis for HVM differs from recovery in case of timely treatment to lethal outcome [1,3].
The worldwide literature describes 31 cases of HVM.
Patients with a suspected focal spinal cord lesion and manifestation of “motor and sensory dissociation” should have differential diagnosis with amyotrophic lateral sclerosis (ALS), which is especially difficult when the neuroinfection is mainly accompanied by segmental and long-tract motor abnormalities with no manifestation of sensory and pelvic disorders which are not typical to ALS. Differential diagnosis of ALS and focal spinal cord lesion is conducted using needle and stimulation myography, spinal cord magnetic resonance imaging (MRI), transcranial magnetic stimulation and, when infectious etiology (myelitis) is suspected, a lumbar puncture and routine CSF analysis, serological reactions and PCR [3, 4].
Patient B., 68 years old, complained of weakness in muscles of the pelvic girdle at walking, lumbar pain at night and after sitting for a long time (the patient had no pain while walking and did not particularly mention any twitching in muscles, either). He was referred to a neurologist for consultation and electromyography by a neurosurgeon, who questioned the fact that the clinical pattern of the disease is caused by complications of vertebral osteochondrosis.
Two months before the examination the patient had herpes zoster. The rash that developed on his left shoulder partially disappeared after treatment with Valacyclovir (Valtrex) in a dose of 500 mg twice a day for one week. However, two weeks later his shoulder started to hurt and walking disorders appeared and gradually aggravated.
It was also found that the patient suffered from bronchial asthma, which was suppressed with Berodual; hormonal drugs (Seretide) was not frequently used – only once or twice per month. In 2009, MRI of the lumbosacral spine revealed retrolisthesis of L2,5 spines, central herniation of disk L1 and central protrusion of the L4-5 (see Figure 1). In 2002, the patient had a stroke with speech impairment. Doppler ultrasound of lower limb vessels did not reveal any pathology.
At physical examination attention was paid to marks from herpes sores in the left supraclavicular region.
In the neurological status no cerebral, meningeal or cognitive disorders or cranial nerve abnormalities were found. Rough palmomental reflexes were observed on the both sides. There were no pareses, atrophies or fasciculations in hands. There was lower extremity paraparesis – up to plegia in toe flexors and extensors, with preservation of the movements in feet. Paresis up to 3b in left hip extensors and up to 3-4b in gluteal muscles, predominantly on the left. Induced fasciculations in the right hip (the anterior group) and left lower leg (calf muscles). Tendon reflexes in upper extremities were moderately brisk, more on the left side, in lower extremities they were dramatically brisk; carpal muscle reflexes (Rossolimo sign), the Babinski sign and Bechterew-Marie-Foix reflexes (spinal automatism or defense reflexes), and plantar muscle (Rossolimo) reflexes on the left side were present. The abdominal reflexes were not elicited. Hypotrophy of toe extensors. Hyperesthesia in the left supraclavicular region where rash marks were found. Hypalgesia of the right lower leg and toes. Coordination was intact. No pelvic disorders were detected.
Figure 1. Spondylodiscitis at the level of T12 spine in patient B. (2009).
Stimulation and needle electroneuromyography was performed. Stimulation electroneuromyography was used to examine peroneal, femoral and sural nerves. M-response amplitude in n. femoralis sin. was reduced – 2.07 mV (with the norm above 3.5 mV), distal latency of M-response was 4.35 ms (with the norm below 5 ms). The M-response had axonal alterations. M-response amplitude in n. femoralis dext. was reduced – 2.74 mV (with the norm above 3.5 mV), distal latency of M-response was increased – 7.5 ms. The M-response had axonal alterations. M-response amplitude in n. peroneus sin. was 4.3 mV (with the norm above 3.5 mV). Distal latency of M-response was 3.4 ms (with the norm below 6.2 ms). RL 1.95 ms (with the norm below 3 ms). No conduction blocks. M-responses of regular shape. Nerve conduction velocity (NCV) in the lower leg was 34.5 m/s (with the norm above 40 m/s), in the fibular channel – 52.1 m/s (within the normal range). F-wave: the NCV range was 36-41 m/s (with the norm above 30 m/s), with 6/20 dropouts, 8 giant responses, no repeated ones. Amplitude of M-response n. peroneus dext. was 4.37 mV (within the normal range). Distal latency of M-response was 4.5 ms (within the normal range). RL was increased – 3.12 ms (with the norm below 3 ms). No conduction blocks. M-responses of regular shape. NCV in the lower leg was decreased – 36.2 m/s (with the norm above 40 m/s), in the fibular channel – 63.6 m/s (within the normal range). F-wave: the NCV range was 40-42 m/s (with the norm above 30 m/s), with 1/20 dropouts. No repeated polyphasic responses, 6 giant responses. Amplitude of sensor activity potential in n. suralis dext. was reduced – 4.59 μV (with the norm above 6 mV), NCV was reduced – 34.1 m/s (with the norm above 40 m/s). Amplitude of sensor activity potential in n. suralis sin. was 9.39 μV (within the normal range), NCV was 22.9 m/s (reduced). Based on stimulation electroneuromyography the following conclusion was made: axonopathy of femoral nerves with demyelination on the right. Bilateral pyramidal insufficiency. Demyelination of calf muscles with axonopathy on the left. Mild demyelination of peroneal nerves. Roots of peroneal nerves are not affected.
Needle myography was used to examine left lateral latissimus, anterior tibialis, deltoid muscles and extensor digitorum muscle on the right.
In m. deltoideus dext. on the left spontaneous activity (SA) represented by 1 fasciculation potential was observed. Average MUAP duration 12.07 ms with the norm of 12.3 ms – increased by 1,9% (with the norm of +/-13%). Average MUAP amplitude was increased – 1235 μV (with the norm of 300-850 μV), the maximum MUAP amplitude was increased – 5922 μV (with the norm below 1200 μV). Polyphasic MUAPs 20% (with the norm below 5%). Normal MUAPs predominate. The recruitment pattern is normal. Stage 3 denervation-reinnervation process (DRP) was revealed.
In m. vastus lateralis on the left SA in the form of 4 fibrillation potentials, 5 fasciculation potentials and 1 positive sharp wave was detected. Average MUAP duration was 13.3 ms with the age norm of 13 ms – increased by 2% (with the norm of +/-13%). Average MUAP amplitude was increased – 1406 μV (with the norm of 300-850 μV), the maximum MUAP amplitude was increased – 2954 μV (with the norm below 1200 μV). Polyphasic MUAPs 20% (with the norm below 5%). Neuronal MUAPs were present. The recruitment pattern is poor. Stage 3 DRP was revealed.
In m. tibialis anterior on the left no SA was detected. Average MUAP duration 13.3 ms with the age norm of 12.3 ms – increased by 7,6% (with the norm of +/-13%). Average MUAP amplitude was increased – 926 μV (with the norm of 300-850 μV), the maximum MUAP amplitude was increased – 8614 μV (with the norm below 1200 μV). Polyphasic MUAPs 20% (with the norm below 5%). Normal MUAPs predominate. The recruitment pattern is poor. Stage 3 DRP was revealed.
In m. extensor digitorum communis on the right SA in the form of 1 fibrillation potentials was revealed. Average MUAP duration 9.45 ms with the age norm of 11.4 ms – increased by 17,1% (with the norm of +/-13%). Average MUAP amplitude was increased – 1232 μV (with the norm of 300-850 μV), the maximum MUAP amplitude was increased – 7017 μV (with the norm below 1200 μV). Polyphasic MUAPs 35% (with the norm below 5%). Neural MUAPs predominate. The recruitment pattern is normal. Stage 1 DRP was diagnosed.
Based on results of needle myography the following conclusion was made: in the muscle of the left thigh a combination of acute and chronic denervation of the neuropathy type was revealed. At the same time, in other examined muscles (left lower leg, left shoulder, left forearm) spontaneous activity is absent or sporadic and there are signs of complete neurogenic devervation.
Thus, clinical and electromyographic examination showed the syndrome of focal lesion of the lumbar enlargement of the spinal cord (current neuronal denervation at this level, reduced excitability of femoral nerves, signs of pyramidal insufficiency) in combination with sensory polyneuropathy. The examination of muscles at other levels excluded ALS, i.e. a generalized neuronal process. Based on the patient’s medical history (probable immunodeficiency due to chronic treatment with steroids and herpes zoster, from which the patient suffered before development of the described complaints), herpetic cervical ganglionitis complicated with subacute (which developed 1 to 3 months before) herpes virus myelitis of the lumbar enlargement was suspected. The patient was consulted by an infectious disease specialist and hospitalized due to indications to in-patient treatment.
Figure 2. No signs of myelitis in the thoracic spinal cord.
Results of inpatient examination: complete blood count – Hb 135 g/l, erythrocytes 4.4, leukocytes 8.1, segmented neutrophils 61, eosinophils 2, lymphocytes 25, monocytes 12, ESR 16. Biochemical blood assay — total protein 61 g/L, creatinine 102 μmol/l, cholesterol 4.9 mmol/l, bilirubin 8 μmol/l, potassium 3.9 mmol/l, sodium 140 mmol/l, ALT 14, AST 13. Urinalysis – specific gravity 1.0016, color – yellow, transparent, leukocytes 2-3 per HPF, no glucose, no protein. Serological blood tests for HIV and syphilis are negative. Routine CSF analysis – colorless, transparent liquid, protein 0.91 g/l, Pandy's reaction – positive, cytosis – 3/3 2 neutrophils, 1 lymphocyte. CSF PCR (Varicella zoster) – negative. Blood PCR (Varicella zoster) – negative. Serodiagnosis (Varicella zoster) — IgG 6,3++ IgM5,4++ (both antibodies detected). MRI of the thoracic spinal cord – spinal cord with clear and smooth contours without structural and volumetric changes. Severe disk dehydration with prolapses up to 2-3.5 mm, to the largest extent – at the level of T8-9 (Figure 2). MRI of the lumbar spine – well pronounced spondylarthritis. Right-sided paramedian herniation of L1-2, left-sided paramedian herniation of L2-3, posterior paramedian herniation of L4-5, flattening of the lumbar lordosis, retrolisthesis of L1, L2, L5 spines (Figure 3). ECG – left ventricular hypertrophy, heart rate 57, sinus rhythm. Fluorography – sings of emphysema, pulmonary fibrosis. MRI of the left knee joint – deforming osteoarthritis and grade 1-2 chondromalacia.
Final diagnosis: cervical herpetic gangliitis. Subacute herpes virus myelitis caused by the herpes zoster virus. Osteochondrosis of the thoracic spine, spondylosis and instability of the lumbar spine. Sensorimotor axonal-demyelinating polyneuropathy of the lower extremities. 3 grade encephalopathy.
The patient underwent antiviral therapy: Aciclovir (Zovirax) 5 ml per 200 ml of sodium chloride physiological solution – 15 infusions; Dibazol 2 ml twice a day i.m.
During the treatment, in the neurological status regression of fasciculations in the left hip and lower leg was observed, the patient began to walk without a stick, paresis severity decreased in the gluteal muscles to 4 points on the left.
Considering the details of the above case, it should be noted that the clinical pattern of the disease resembled the onset of ALS and actually corresponded to the criteria of “probable” ALS . The patient had a combination of symptoms of impairment of peripheral (PMN) and central (CMN) mononeurons at two levels – thoracic and lumbar, absence of abdominal reflexes, fasciculations in the right hip and left lower leg, lower mixed paraparesis, hypotrophy of foot muscles, hyperreflexia in legs with pathological pyramidal signs. However, some symptoms of CMN impairment were more rostral than in PMN – carpal pathological signs, palmomental (Marinesko) reflexes. But the latter could be attributed to the manifestation of vascular encephalopathy. There were no pelvic disorders and sensory abnormalities were minimal and of segmental nature. Decisive in the differential diagnosis of ALS were needle myography findings that supposed localization of the denervation process. The diagnosis of subacute herpes virus myelitis was confirmed by the routine CSF test (increased protein content). Pleocytosis was not detected, probably, due to early treatment. Results of serological blood tests of the patient (increased titer of “acute” IgM and “deferred” IgG) only show an acute herpetic infection, however, taking into account ganglionitis in the cervical region, they do not clearly indicate the localization. Blood and CSF PCRs were not informative in this case as evidenced in the literature. MRI of the thoracic spinal cord did not clearly reveal the myelitis focus, either, probably, due to the fact that the antiviral treatment was started before the MRI. During the antiviral treatment regression of neurological symptoms was achieved and impaired functions were restored.
Figure 3. Apparent spondyloarthritis, herniation of L1-2, retrolisthesis of L1-2.
The peculiarity of this case is the background of immunodeficiency (see Figure 1). However, the process was localized at the level of those spine segments that corresponded to the spinal cord segments infected with a herpes virus. Probably, the hematomyelitic barrier had been weakened, which caused the development of the lumbar enlargement instead of, for example, the cervical department where the herpes zoster initially appeared. The etiology of sensory axonal-demyelinating polyneuropathy in the patient also remains insufficiently clear.
No conflict of interest.
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