An Evolving Understanding of ALS with Frontotemporal Degeneration



Partners in FTD Care, Spring 2018
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Amyotrophic lateral sclerosis (ALS), also called “Lou Gehrig’s disease,” is caused by the death of motor neurons, nerve cells that control voluntary muscles. Doctors and researchers are increasingly recognizing that many people with ALS also experience cognitive changes consistent with FTD. Indeed, as many as half of those with ALS exhibit behavioral changes or a decline in language skills similar to those observed in behavioral variant FTD or primary progressive aphasia. Conversely, up to 30% of people diagnosed with FTD develop motor symptoms consistent with ALS.

Over the last 10 years, there has been increasing recognition of a continuum between ALS and FTD that can be characterized on clinical, imaging, and pathological grounds. The recent discovery that mutation of the C9orf72 gene is the most common genetic cause of both disorders offers further evidence of this continuum. ALS with FTD is an especially complicated and challenging form of FTD, and our understanding of it is still evolving.

The Case of Cathy R.

 
Early Symptoms and Diagnosis

While in her early 60s, Cathy R. began slurring her speech, a condition called dysarthria. After six months of these symptoms, she and her husband Michael visited the neuromuscular disorders clinic at an academic medical center for evaluation. Michael explained that she did not like to talk because she was embarrassed by her speech, so he presented most of her history. He said her primary care doctor was concerned about the possibility of a stroke, and ordered an MRI scan of her brain. While the scan came back normal, her symptoms grew more consistent, and her doctor referred her to a neurologist.

The neurologist suspected myasthenia gravis, an autoimmune disorder that causes muscle weakness, and ordered blood work to confirm a diagnosis. As with her MRI scan, Cathy’s blood work came back normal. Yet her neurologist continued to suspect myasthenia and prescribed Mestinon, a medication that alleviates its symptoms. She and Michael both thought that the Mestinon improved her speech.

During a follow-up appointment with the neurologist, Michael reported that she had tripped and fallen twice and wondered if this was a common problem in myasthenia. Additionally, she had developed muscle cramps in her legs. The neurologist believed that the Mestinon most likely caused the cramps. He prescribed Robinul to counteract them and discussed adding prednisone, a steroid, to treat Cathy’s apparent leg weakness.

At the next monthly follow-up, Cathy reported that she had lost four pounds and had fallen again. Her neurologist noted a new hyperactive knee reflex and consequently questioned his diagnosis of myasthenia gravis. He referred her to a specialist in neuromuscular disorders for a second opinion.

The specialist took note of Cathy’s most prominent symptoms: dysarthria, mild dysphagia (difficulty swallowing), muscle cramps, and multiple falls. She had lost a total of seven pounds over three months, which she ascribed to a poor appetite. Asked whether she had been more frequently laughing, crying or yawning, she smiled and shook her head “no,” but her husband nodded: Yes, he had noticed that recently. A physical examination showed marked paucity of speech; she largely communicated by nodding and giving one-word answers. She giggled often and looked to her husband to complete her sentences. They examined her family history: Both of her parents died in a car accident when she was 38, while her maternal aunt had been diagnosed with dementia in her mid-50s — “but not the kind that makes you lose your keys or get lost,” as Cathy put it. (Her aunt lived eight more years after her diagnosis before dying of pneumonia.)

The specialist evaluated her upper and lower motor neuron responses for indicators of damage to the nerve paths connecting the brain and spinal cord. She observed dysarthria, mild facial weakness, and evidence of tongue weakness, as well as fasciculations (twitching) in the tongue, right upper arm, and both upper and lower legs. Cathy’s gait showed right foot drop due to right ankle weakness. Reflexes were normal in the arms and “brisk” in the legs, meaning they contracted several times when tested; Babinski signs, reflexes that occur when the sole of the foot is stimulated, were not present. The physical exam indicated upper motor neuron involvement in the bulbar region of the brain and the lumbosacral (lower spine) area, and lower motor neuron involvement in the bulbar, cervical and lumbosacral segments with additional features suggestive of primary progressive aphasia.

Privately, the doctor determined that results of the examination were consistent only with a diagnosis of ALS with FTD; no other diagnostic considerations would account for all of her symptoms and signs. However, other conditions could potentially account for some of Cathy’s symptoms, so additional tests will be needed to rule out those diagnoses.

The doctor explained that she did not have myasthenia gravis, and that further testing was needed. Michael asked what she thought was wrong with his wife. The doctor explained that the problem appeared to be with her motor nerves or neurons, and that she would have to do a few tests to be sure. Michael then said he had been reading about ALS – could that be the problem? The doctor said she was quite concerned that ALS was, in fact, the diagnosis, and she expected that additional tests would support this suspicion. There is no one specific test to confirm ALS, the doctor explained; additional tests are mostly to exclude other potential causes of the symptoms. Cathy paid intermittent attention during this discussion.

An Expanded Diagnosis

Over the next two weeks, electrodiagnostic studies showed the expected nerve damage, while MRIs and blood work failed to point toward an alternative diagnosis. The couple returned for a follow-up visit to the multi-disciplinary ALS clinic. They first met with the specialist to discuss a formal diagnosis. She said that Cathy’s reduced language production suggested primary progressive aphasia, thus expanding the diagnosis from ALS to ALS with FTD. Cathy shook her head, and Michael said that her lack of speech production was due to her discomfort with her slurring, not FTD. “She understands everything, you can be sure of that!” he said. When the doctor asked her to write a sentence about the weather, she wrote, “tody sunny cold.” However, because visits to the multidisciplinary clinic can be lengthy, the doctor did not pursue the issue of language production at that time.

During their first official clinic visit, Cathy and Michael met with a nurse practitioner, physical therapist, occupational therapist, speech and language pathologist, dietitian, research nurse coordinator, genetic counselor, and a representative from a nonprofit ALS care organization; a follow-up phone call with a social worker was also arranged. At the end of the clinic day, the team met to discuss their observations. All team members said they noticed that she spoke very little and laughed inappropriately. Pulmonology function tests showed her breathing was normal, but a swallow evaluation revealed that her swallowing function was significantly worse than she and her husband had reported. The speech and language pathologist recommended thickened liquids, while the physical therapist recommended a brace for her right leg. The genetic counselor had asked the couple if they were interested in pursuing genetic testing, but — overwhelmed by the length of the visit and failing to fully appreciate that the condition might be genetic, and that that information could be of use to other extended family members — they declined. Together, they scheduled a follow-up visit in three months.

Eight weeks later, concerned that his wife was losing weight, Michael called the nurse practitioner to ask if he could move up their appointment. An evaluation showed that Cathy had lost eight pounds since her last visit.

The evaluation indicated progression in other symptoms. Cathy spoke rarely, and when she did her words were nearly unintelligible; she continuously looked to her husband to speak for her. She barely reacted when Michael wiped her face off after she exhibited sialorrhea (drooling). When Michael reported that she would not drink the thickened liquids, she just smiled and laughed. He said that she seemed uninterested in eating, even when he tried to give her foods she liked. In fact, she did not really seem interested in doing much at all. She had stopped socializing with friends, which Michael attributed to her discomfort with the sound of her speech. Oddly enough, while she liked to watch the Food Network all day, this did not seem to spark an interest in actually eating.

New findings from her physical examination included right hand weakness and worsened bilateral leg weakness, making her gait quite unsteady. At the previous visit, Cathy had rejected the idea of a brace for her right foot. This time, the doctor suggested that braces on both feet and a walker would help stabilize her movement. Michael was quite enthusiastic, but his wife smiled and shook her head no. To demonstrate how well she could still move, she stood up to walk, but as she turned she lost her balance and nearly fell over, causing her to laugh uncontrollably. The doctor suggested medication to enhance her appetite and control her drooling. Michael agreed to try, but said that she generally refused to take pills at this point.

When the doctor again brought up language disorders, Michael reiterated that his wife could still speak but chose not to because of the way her voice sounded. The doctor explained the relationship between ALS and FTD and discussed the different forms that FTD can take, focusing on primary progressive aphasia. (While ALS with FTD is most commonly associated with the behavioral variant of FTD, both the non-fluent agrammatic and semantic variants of PPA can occur in association with ALS.) She was very clear with Cathy and Michael that primary progressive aphasia was playing an important role in her disease process, and that certain symptoms of her FTD – including poor judgment and lack of awareness – will make his caregiving responsibilities that much harder. Certain therapies and treatments for ALS will likely be unworkable because of her FTD. The doctor encouraged Michael to try not to get discouraged, although she emphasized that frustration would be common.

After Michael expressed a need for time to process this information, the doctor offered him an appointment with the affiliated cognitive clinic to learn more about FTD and connect with the many resources and supports available from AFTD. Still feeling overwhelmed, Michael said he would call back to schedule that appointment. In the meantime, the doctor encouraged him to focus on Cathy’s safety and nutrition and to try to encourage her to take the new medication for appetite stimulation.

Shifting to Comfort Care

At their follow-up visit four weeks later, Cathy arrived in a transport wheelchair given to them by a member of their church. She looked thinner, having lost an additional six pounds. While she smiled most of the time, she produced no speech, instead making continuous moaning noises. She communicated through facial expressions and by nodding her head. Michael reported that she ate very little food, often holding it in her mouth for a long time before swallowing, and that she would not take any medications at all. She was able to walk minimally with assistance from her bed to the bathroom, and needed help with all activities of daily living. She denied being in pain, and Michael believed her.

Michael did say that he understood that his wife had ALS with FTD after he had done some reading about it. When the neurologist asked if she was interested in doing genetic testing for the benefit of her immediate family, Cathy did not respond. Michael said he did not want to put her through any unnecessary tests – he understood his wife’s poor prognosis and wanted to ensure her safety and comfort during her decline. They began a discussion of hospice care and the types of assistance he would need to continue to care for her at home. Just three weeks later, Cathy died at home, with Michael at her side.

Questions for discussion:

 
What physical symptoms prompted the evaluation with a neurologist who specialized in neuromuscular disorders? What signs of ALS were found?
Initially, Cathy’s most prominent symptom was dysarthria, or slurred speech. An MRI ruled out stroke early, but her dysarthria continued. Soon she started falling occasionally, and experienced muscle cramps and leg weakness. A neurologist suspected myasthenia gravis, an autoimmune disorder. During a follow-up appointment, the neurologist noted weight loss and abnormal reflex responses, and referred her to a specialist.

What language and behavioral symptoms did Cathy exhibit that led the specialist to suspect ALS with FTD?
Early in her evaluation, the specialist noted her consistent lack of speech and inappropriate laughter. Cathy reported some family history of dementia. Michael believed his wife understood everything even though she did not respond, which can be consistent with primary progressive aphasia (PPA). The poor syntax in her simple written sentence was another indicator. She also demonstrated poor self-awareness and judgment when she impulsively tried to prove she could walk and almost fell down. The team at the ALS clinic all noted that lack of speech and inappropriate laughter are not characteristic of ALS alone.

What contributed to Michael’s difficulty recognizing the signs of primary progressive aphasia and their impact on Cathy?
Michael attributed his wife’s reduced speech production to her disliking the sound of her voice, due dysarthria. They both thought the medication, Mestinon, improved her speech. Her communication during appointments was mostly limited to nodding or smiling, which Michael would “translate” into speech for her. They both minimized her family history of dementia because “it was not like the memory kind.” Quickly, however, her rapid progression became overwhelming for her husband. Absorbing her diagnosis and meeting her changing physical needs required all his focus and energy. He read about FTD/ALS and came to terms with his wife’s diagnosis, but chose not to pursue genetic testing.

What was the focus of treatment following diagnosis? When and why did it change?
Cathy’s physical condition deteriorated rapidly. The ALS multidisciplinary clinic evaluation identified needs of ALS symptoms and recommended interventions based on standards of care in ALS – braces and a walker for movement, thickened liquids for easier swallowing, medication to counteract her drooling and encourage her appetite. Michael reported that she refused to wear braces, take her medicine or consume thickened liquid – all signs of cognitive impairment separate from ALS. Her obstinacy added to her husband’s stress – he was trying to follow recommendations and be a good caregiver, but FTD kept interfering. By that point, Michael became more accepting of his wife’s diagnosis. The doctor did not recommend standard ALS interventions, including breathing procedures and a PEG tube for feeding, as Cathy’s PPA and rapid progression made compliance impossible. Michael shifted his focus to comfort care and hospice. It was just 15 months between his wife’s initial presentation of dysarthria to a discussion of hospice care and her passing.

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