We desribe 2 patients of Jewish Libyan descent, who presented with a clinical syndrome compatible with Creutzfeldt- Jakob disease and who were found to have a mutation of codon 200 in the prion protein. The patients developed symptoms and signs of peripheral nerve involvement diagnosed by electrodiagnostic and histopathological studies as demyelinating neuropathy. This may be a rare manifestation of Creutzfeldt-Jakob disease. 0 John Wiley & Sons, Inc.
Key words: Creutzfeldt-Jakob disease prions peripheral neuropathy peripheral neuropathy demyelinating neuropathy MUSCLE & NERVE 15~1234-1239 1992
DEMYELINATING PERIPHERAL NEUROPATHY IN CREUTZFELDTJAKOB DISEASE MIRIAM Y. NEUFELD, MD, JOSEPH JOSIPHOV, MD, AND AMOS D. KORCZYN, MD, MSC
Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disease with distinct clinical and neuropathological features, believed to be transmissible by prions, proteinaceous infectious particles in which an aberrant host protein is a major and necessary component. l 3 A protease-resistant isoform of the prion protein (Prp) accumulates in the brains of patients with CJD.' A positive family history is quite commong and, among Libyan Jews, the disease is at least 30 times more prevalent than in the worldwide p ~ p u l a t i o n .Recently, ~ a mutation of codon 200 in the prion protein gene has been found in Libyan Jews with CJD.4 CJD affects predominantly the brain grey matter, with histopathological evidence of neuronal loss, gliosis, and diffuse spongiform changes. White matter is rarely involved, with extensive degeneration of cerebral white matter, reported 12.18 The disease is usually regarded as affecting only the CNS; however, peripheral demyelination
From the Departments of Neurology (Drs. Neufeld and Korczyn) and Pathology (Dr. Josiphov), Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine. Tel-Aviv University, Tel-Aviv, Israel. Acknowledgments: The authors thank Prof. U. Sandbank for evaluation of the biopsy material. Dr. J. Chapman performed the molecular genetic examination. Address reprint requests to Professor A. D. Korczyn, Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv 69978, Israel. Accepted for publication March 12, 1992. CCC 0148-639)(/92/111234-06 0 1992 John Wiley & Sons, Inc.
1234
Demyelinating Neuropathy in CJD
was described in a single patient with familial CJD of the panencephalitis form,lg and in 1 additional sporadic case in 1 ~ r a e l . l ~ We hereby report 2 patients with a mutation of the codon 200 prion protein gene and peripheral neuropathy of a demyelinating type. CASE REPORTS
I. A 60-year-old man, born in Libya, immigrated to Israel at age 30. He had been in good health, except for left nephrectomy because of renal calculi at the age of 48. An older brother had died at the age of 71 of clinically diagnosed, bopsy confirmed CJD. Walking difficulties, instability, and frequent falls had started 2 months prior to his hospitalization. Subsequently, a confusional agitative state developed, to be followed within a few weeks by speech difficulties and bradykinesia. He gradually deteriorated and became disoriented in time and place, able to obey only simple commands, and had difficulties in writing, reading, and calculating. On neurological examination there was some limitation of upward gaze. There was no obvious muscle atrophy. Occasional fasciculations were seen in the lower limbs. Motor examination revealed normal strength deep tendon reflexes were normal in the upper extremities but absent in the legs. Pinprick and light touch sensations were decrease in a glove-and-stocking distribution. Vibra-
Case
MUSCLE & NERVE
November 1992
tion and position sense were intact. The nerves were not thickened on palpation. He walked on a wide base and there was mild gait and limb ataxia. Myoclonias were not observed. Normal laboratory findings included red and white count, serum glucose, electrolytes, kidney and liver function tests, protein electrophoresis, thyroid function tests, vitamin B12, folic acid, antinuclear factor, hexosaminidase A, as well as urinary porphyrins, heavy metals, and Bence- Jones protein. Cerebrospinal fluid pressure was normal with 160 mg/dL protein, 50 mg/dL glucose, and 1 ~ e l l / m mC . ~T of the brain with and without contrast showed generalized mild atrophy. EEG recordings revealed generalized nonspecific slowing in the theta and delta range, without periodic activity. Biopsy of the sural nerve showed no abnormalities. Brain biopsy (right frontal lobe) was performed and light microscopy revealed diminution in the number of neurons and slight astrocytosis. On electron microscopy, swelling of the neurons and vacuoles surrounded by definite membranes in nerve and glial processes were noted. The patient had the codon 200 mutation in Prion protein gene (case 1).5 In transmission experiments his brain tissue transmitted a spongiform encephalopathy to a chimpanzee following 60 months of incubation. The patient continued to deteriorate, and became severely demented, incontinent, bedridden, and finally noncommunicative. He was transferred elsewhere and died approximately 18 months after the onset of the disease. Autopsy was not performed. A 57-year-old man, born in Libya, immigrated to Israel at age 17. His past history was unremarkable. He was admitted to our department because of difficulties in walking and dysarthria, which had started approximately 2 months previously. One sister was hospitalized elsewhere at the age of 65 years with cognitive deterioration. Meningioma was found on brain CT. In spite removal of the tumor, her mental functions continued to deteriorate and she died less than 1 year following the operation with profound dementia. Autopsy was not permitted. The patient’s general physical examination was unremarkable. On neurological examination, very mild cognitive impairment was apparent. He was dysarthric but all other cranial nerves were normal. In the limbs, strength and muscle tone were normal and there was no muscular atrophy. Case 2.
Demyelinating Neuropathy in CJD
Prominent and diffuse fasciculations were apparent in all extremities. Deep tendon reflexes were brisk and plantar responses were flexor. There was prominent action tremor in the hands and slight dysmetria on the finger-to-nose and the heel-to-shin test. Gait was broad-based and atactic. Sensation was normal to touch, pin prick, vibration, joint position, and two-point discrimination. The patient continued to deteriorate. He lost his patellar and ankle reflexes. He developed profound dementia and later became almost mute and incontinent, as well as increasingly rigid and atactic, and finally died approximately 12 months following the onset of disease. Normal laboratory findings included red and white blood cell count, serum glucose, urea, electrolytes, hepatic and renal functions, protein electrophoresis, CEA, thyroid function tests, B 12, folic acid, and hexosaminidase A. Elevated antiGM1 IgM antibody titers were found. The level of anti GM1 was determined by solid phase radioimmunoassay (levels are considered to be abnormal above 1.5 binding index units). In our patient, the level of the antibodies was 2.7 binding index units. Urinalysis was without abnormal findings. BenceJones protein and heavy metals were not found. Lumbar puncture showed normal pressure, 40 mg/dL protein, 60 mg/dL glucose, and no abnormal cells. The presence of codon 200 mutation in the prion protein gene was confirmed (case 2).5 Repeated EEG tracings showed diffuse theta and delta waves and occasional triphasic waves, but no periodic activity. Brain C T and MRI were interpreted as normal. Brain biopsy (right frontal cortex) was performed, and revealed vacuolation of the neuropil in addition to gliosis (Fig. 1). Sural nerve biopsy was performed. Longitudinal paraffin sections were stained with hematoxylin and eosin as well as luxol fast blue. The fibers demonstrated prominent and widespread segmental demyelination (Fig. 2). METHODS
Electrophysiological studies were performed on a Teca electromyograph in patient 1 and on a Medelec Mystro electromyograph in patient 2. Motor responses were recorded with surface electrodes that were positioned to give an initial negative deflection. Motor nerve conduction studies were performed with percutaneous supramaximal nerve stimulation. Compound muscle action potentials (CMAP) ampltidues were measured from baseline to negative peak. The CMAP amplitudes and the area under the curve were calculated in patient 2,
MUSCLE 8, NERVE
November 1992
1235
FIGURE 1. Patient 2: biopsy of right frontal lobe: empty vacuoles impinging on neuronal nuclei (arrows). H&E, x400.
by the built-in computerized program of the electromyograph. We defined motor conduction block as being present with the reduction in CMAP amplitude of SO%, and the total area beneath the evoked response on proximal stimulation less than 60% of the area obtained on distal s ti mu la ti on.^ F-wave latencies from at least 10 responses were recorded with the same surface disc electrodes fol-
lowing stimulation at the wrist or ankle. Sensory nerve action potentials were recorded antidromically using surface ring electrodes. Skin temperature was maintained above 30°C for all studies. RESULTS Case 1. Electromyography showed occasional fibrillation potentials and fasciculations in the ante-
FIGURE 2. Patient 2: biopsy of a sural nerve showing segmental demyelination (arrows). Lux01 fast blue, x400.
1236
Dernyelinating Neuropathy in CJD
MUSCLE & NERVE
November 1992
rior tibial muscles bilaterally, as well as polyphasic long duration units with decreased recruitment. Nerve conduction studies showed normal CMAP in the median, ulnar, tibial, and peroneal nerves bilaterally, prolonged distal motor latencies and slow conduction velocities in both peroneal nerves (distal delay 7.5 to 10 ms, velocity 21 to 23 m/s, normal ranges 3 to 6.5 ms and 41 to 59 m/s, respectively), posterior tibial nerve (distal delay 7.5 ms, velocity 27 ms, normal ranges 3.3 to 6.0 and 41 to 58, respectively), and median motor (distal delay 3 ms, velocity 42 ms, normal ranges 2.2 to 4.0 ms and 49 to 70 m/s, respectively). Distal delay and conduction velocity of the right median nerve were normal. No response was obtained following sural nerves stimulation.
Electrodiagnostic studies were obtained on admission and 6 weeks later. Electromyography showed diffuse fasciculations and occasional fibrillations. The units were slightly polyphasic with normal amplitudes and almost normal recruitment pattern in proximal and distal muscles in all extremities. In addition, prolonged distal latencies, decreased velocities, and dispersion of the compound muscle potential (CMAP) as well as multifocal conduction blocks were observed, with reduction in CMAP amplitude which could not have been accounted for by dispersion (Table 1). Case 2.
DISCUSSION
Both of our patients had clinical features typical of CJD, and the diagnosis was confirmed by the
Table 1. Nerve conduction studies in patient 2 Amplitude (motor, mV; sensory, kV)
RT
Area under the curve (mV/ms)
LT*
RT
Distal delay (ms)
Cond. velocity (m/s)
F wave (ms)
LT
Wrist
Elbow
Wrist
Elbow
Wrist
Elbow
RT
LT
1.6 0.6
5.0 2.2
2.5 0.9
4.7 3.0
3.0 2.1
8.5 3.3
4.5 1.1
(2.2) 0.8 First exam 1.0 Second exam Tibia1
Ankle
First exam Second exam
(>4.0) 2.0 1.6
RT
LT
RT
LT
(
Key words: Creutzfeldt-Jakob disease prions peripheral neuropathy peripheral neuropathy demyelinating neuropathy MUSCLE & NERVE 15~1234-1239 1992
DEMYELINATING PERIPHERAL NEUROPATHY IN CREUTZFELDTJAKOB DISEASE MIRIAM Y. NEUFELD, MD, JOSEPH JOSIPHOV, MD, AND AMOS D. KORCZYN, MD, MSC
Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disease with distinct clinical and neuropathological features, believed to be transmissible by prions, proteinaceous infectious particles in which an aberrant host protein is a major and necessary component. l 3 A protease-resistant isoform of the prion protein (Prp) accumulates in the brains of patients with CJD.' A positive family history is quite commong and, among Libyan Jews, the disease is at least 30 times more prevalent than in the worldwide p ~ p u l a t i o n .Recently, ~ a mutation of codon 200 in the prion protein gene has been found in Libyan Jews with CJD.4 CJD affects predominantly the brain grey matter, with histopathological evidence of neuronal loss, gliosis, and diffuse spongiform changes. White matter is rarely involved, with extensive degeneration of cerebral white matter, reported 12.18 The disease is usually regarded as affecting only the CNS; however, peripheral demyelination
From the Departments of Neurology (Drs. Neufeld and Korczyn) and Pathology (Dr. Josiphov), Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine. Tel-Aviv University, Tel-Aviv, Israel. Acknowledgments: The authors thank Prof. U. Sandbank for evaluation of the biopsy material. Dr. J. Chapman performed the molecular genetic examination. Address reprint requests to Professor A. D. Korczyn, Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv 69978, Israel. Accepted for publication March 12, 1992. CCC 0148-639)(/92/111234-06 0 1992 John Wiley & Sons, Inc.
1234
Demyelinating Neuropathy in CJD
was described in a single patient with familial CJD of the panencephalitis form,lg and in 1 additional sporadic case in 1 ~ r a e l . l ~ We hereby report 2 patients with a mutation of the codon 200 prion protein gene and peripheral neuropathy of a demyelinating type. CASE REPORTS
I. A 60-year-old man, born in Libya, immigrated to Israel at age 30. He had been in good health, except for left nephrectomy because of renal calculi at the age of 48. An older brother had died at the age of 71 of clinically diagnosed, bopsy confirmed CJD. Walking difficulties, instability, and frequent falls had started 2 months prior to his hospitalization. Subsequently, a confusional agitative state developed, to be followed within a few weeks by speech difficulties and bradykinesia. He gradually deteriorated and became disoriented in time and place, able to obey only simple commands, and had difficulties in writing, reading, and calculating. On neurological examination there was some limitation of upward gaze. There was no obvious muscle atrophy. Occasional fasciculations were seen in the lower limbs. Motor examination revealed normal strength deep tendon reflexes were normal in the upper extremities but absent in the legs. Pinprick and light touch sensations were decrease in a glove-and-stocking distribution. Vibra-
Case
MUSCLE & NERVE
November 1992
tion and position sense were intact. The nerves were not thickened on palpation. He walked on a wide base and there was mild gait and limb ataxia. Myoclonias were not observed. Normal laboratory findings included red and white count, serum glucose, electrolytes, kidney and liver function tests, protein electrophoresis, thyroid function tests, vitamin B12, folic acid, antinuclear factor, hexosaminidase A, as well as urinary porphyrins, heavy metals, and Bence- Jones protein. Cerebrospinal fluid pressure was normal with 160 mg/dL protein, 50 mg/dL glucose, and 1 ~ e l l / m mC . ~T of the brain with and without contrast showed generalized mild atrophy. EEG recordings revealed generalized nonspecific slowing in the theta and delta range, without periodic activity. Biopsy of the sural nerve showed no abnormalities. Brain biopsy (right frontal lobe) was performed and light microscopy revealed diminution in the number of neurons and slight astrocytosis. On electron microscopy, swelling of the neurons and vacuoles surrounded by definite membranes in nerve and glial processes were noted. The patient had the codon 200 mutation in Prion protein gene (case 1).5 In transmission experiments his brain tissue transmitted a spongiform encephalopathy to a chimpanzee following 60 months of incubation. The patient continued to deteriorate, and became severely demented, incontinent, bedridden, and finally noncommunicative. He was transferred elsewhere and died approximately 18 months after the onset of the disease. Autopsy was not performed. A 57-year-old man, born in Libya, immigrated to Israel at age 17. His past history was unremarkable. He was admitted to our department because of difficulties in walking and dysarthria, which had started approximately 2 months previously. One sister was hospitalized elsewhere at the age of 65 years with cognitive deterioration. Meningioma was found on brain CT. In spite removal of the tumor, her mental functions continued to deteriorate and she died less than 1 year following the operation with profound dementia. Autopsy was not permitted. The patient’s general physical examination was unremarkable. On neurological examination, very mild cognitive impairment was apparent. He was dysarthric but all other cranial nerves were normal. In the limbs, strength and muscle tone were normal and there was no muscular atrophy. Case 2.
Demyelinating Neuropathy in CJD
Prominent and diffuse fasciculations were apparent in all extremities. Deep tendon reflexes were brisk and plantar responses were flexor. There was prominent action tremor in the hands and slight dysmetria on the finger-to-nose and the heel-to-shin test. Gait was broad-based and atactic. Sensation was normal to touch, pin prick, vibration, joint position, and two-point discrimination. The patient continued to deteriorate. He lost his patellar and ankle reflexes. He developed profound dementia and later became almost mute and incontinent, as well as increasingly rigid and atactic, and finally died approximately 12 months following the onset of disease. Normal laboratory findings included red and white blood cell count, serum glucose, urea, electrolytes, hepatic and renal functions, protein electrophoresis, CEA, thyroid function tests, B 12, folic acid, and hexosaminidase A. Elevated antiGM1 IgM antibody titers were found. The level of anti GM1 was determined by solid phase radioimmunoassay (levels are considered to be abnormal above 1.5 binding index units). In our patient, the level of the antibodies was 2.7 binding index units. Urinalysis was without abnormal findings. BenceJones protein and heavy metals were not found. Lumbar puncture showed normal pressure, 40 mg/dL protein, 60 mg/dL glucose, and no abnormal cells. The presence of codon 200 mutation in the prion protein gene was confirmed (case 2).5 Repeated EEG tracings showed diffuse theta and delta waves and occasional triphasic waves, but no periodic activity. Brain C T and MRI were interpreted as normal. Brain biopsy (right frontal cortex) was performed, and revealed vacuolation of the neuropil in addition to gliosis (Fig. 1). Sural nerve biopsy was performed. Longitudinal paraffin sections were stained with hematoxylin and eosin as well as luxol fast blue. The fibers demonstrated prominent and widespread segmental demyelination (Fig. 2). METHODS
Electrophysiological studies were performed on a Teca electromyograph in patient 1 and on a Medelec Mystro electromyograph in patient 2. Motor responses were recorded with surface electrodes that were positioned to give an initial negative deflection. Motor nerve conduction studies were performed with percutaneous supramaximal nerve stimulation. Compound muscle action potentials (CMAP) ampltidues were measured from baseline to negative peak. The CMAP amplitudes and the area under the curve were calculated in patient 2,
MUSCLE 8, NERVE
November 1992
1235
FIGURE 1. Patient 2: biopsy of right frontal lobe: empty vacuoles impinging on neuronal nuclei (arrows). H&E, x400.
by the built-in computerized program of the electromyograph. We defined motor conduction block as being present with the reduction in CMAP amplitude of SO%, and the total area beneath the evoked response on proximal stimulation less than 60% of the area obtained on distal s ti mu la ti on.^ F-wave latencies from at least 10 responses were recorded with the same surface disc electrodes fol-
lowing stimulation at the wrist or ankle. Sensory nerve action potentials were recorded antidromically using surface ring electrodes. Skin temperature was maintained above 30°C for all studies. RESULTS Case 1. Electromyography showed occasional fibrillation potentials and fasciculations in the ante-
FIGURE 2. Patient 2: biopsy of a sural nerve showing segmental demyelination (arrows). Lux01 fast blue, x400.
1236
Dernyelinating Neuropathy in CJD
MUSCLE & NERVE
November 1992
rior tibial muscles bilaterally, as well as polyphasic long duration units with decreased recruitment. Nerve conduction studies showed normal CMAP in the median, ulnar, tibial, and peroneal nerves bilaterally, prolonged distal motor latencies and slow conduction velocities in both peroneal nerves (distal delay 7.5 to 10 ms, velocity 21 to 23 m/s, normal ranges 3 to 6.5 ms and 41 to 59 m/s, respectively), posterior tibial nerve (distal delay 7.5 ms, velocity 27 ms, normal ranges 3.3 to 6.0 and 41 to 58, respectively), and median motor (distal delay 3 ms, velocity 42 ms, normal ranges 2.2 to 4.0 ms and 49 to 70 m/s, respectively). Distal delay and conduction velocity of the right median nerve were normal. No response was obtained following sural nerves stimulation.
Electrodiagnostic studies were obtained on admission and 6 weeks later. Electromyography showed diffuse fasciculations and occasional fibrillations. The units were slightly polyphasic with normal amplitudes and almost normal recruitment pattern in proximal and distal muscles in all extremities. In addition, prolonged distal latencies, decreased velocities, and dispersion of the compound muscle potential (CMAP) as well as multifocal conduction blocks were observed, with reduction in CMAP amplitude which could not have been accounted for by dispersion (Table 1). Case 2.
DISCUSSION
Both of our patients had clinical features typical of CJD, and the diagnosis was confirmed by the
Table 1. Nerve conduction studies in patient 2 Amplitude (motor, mV; sensory, kV)
RT
Area under the curve (mV/ms)
LT*
RT
Distal delay (ms)
Cond. velocity (m/s)
F wave (ms)
LT
Wrist
Elbow
Wrist
Elbow
Wrist
Elbow
RT
LT
1.6 0.6
5.0 2.2
2.5 0.9
4.7 3.0
3.0 2.1
8.5 3.3
4.5 1.1
(2.2) 0.8 First exam 1.0 Second exam Tibia1
Ankle
First exam Second exam
(>4.0) 2.0 1.6
RT
LT
RT
LT
(
